P

Palatinose®

Palatinose® is the commercial product isomaltose, obtained from sucrose by enzymatic rearrangement followed by crystallization (Scheme P.41). It is found naturally in honey (Barez et al., 2000) and products derived from sugar-cane juice, such as treacles and molasses (Takazoe, 1985). Unlike sucrose, a nonreducing disaccharide in which glucose and fructose are linked α-1,2, isomaltose is a reducing disaccharide in which glucose and fructose are linked α-1,6. As a result, palatinose is hardly fermented by oral microbes and appeared to be a suitable noncariogenic sucrose replacement for incorporation into products for diabetics (Kawai et al., 1989).

In vivo studies with rats and pigs showed it is completely hydrolyzed and absorbed in the small intestine. However, the rate of hydrolysis was very slow compared to sucrose or maltose so that in humans the rise of blood glucose and insulin levels after oral administration was slower, reaching lower maxima compared to sucrose. No embryotoxic or terratogenic effects were observed in rat fetuses, nor maternal toxicity at levels up to 7 g/kg body weight/day (Lina et al., 2002). Using the Ames test, they found isomaltose was nonmutagenic and was a safe alternative sugar. Dietary levels of up to 10 percent isomaltose were shown by Jonker et al. (2002) to be well tolerated without any signs of toxicity. The overall intake at this level corresponded to 7.0 and 8.1 g/kg body weight/day in male and female rats, respectively.

Although palatinose appears to be a noncariogenic disaccharide and unable to be utilized by Streptoccus mutans, Matsuyama et al. (2003) showed there were still a significant number of bacteria in dental plaque capable of fermenting it. Using the Uchida-Kraepelin psychodiagnostic test, Kashimura et al. (2003) found that 5 g of palatinose enhanced mental concentration by increasing calculation ability.

References

Gomez Barez, J.A., Villanova, R.J.G., Garcia, S.E., Pala, T.R., Paramas, A.M.G., and Sanchez, J.S., Geographical discrimination of honeys through the employment of sugar patterns and common chemical quality parameters, Eur. Food Res. Technol., 210: 437–444, 2000.

Jonker, D., Lina, B.A., and Kozianowski, G., 13-Week oral toxicity study with isomaltulose (Palatinose) in rats, Food Chem. Toxicol., 40:1383–1389, 2002.

Kashimura, J., Nagai, Y., and Ebashi, T., The effect of palatinose on mental concentration in humans, J. Nutr. Sci. Vitaminol., 49:214–216, 2003.

Kawai, K., Yoshikawa, H., Murayama, Y., Okuda, Y., and Yamashita, K., Usefulness of palatinose as a caloric sweetener for diabetic patients, Horm. Metab. Res., 21:338–340, 1989.

Lina, B.A., Jonker, D., and Kozianowski, G., Isomaltose (Palatinose^®): A review of biological and toxicological studies, Food Chem. Toxicol., 40:375–381, 2002.

Matsuyama, J., Sato, T., Hoshino, E., Noda, T., and Takahashi, N., Fermentation of five sucrose isomers by human dental plaque bacteria, Caries Res., 37: 410–415, 2003.

Takazoe, Y., New trends on sweeteners in Japan, Int. Dental J., 35:58–65, 1985.

SCHEME P.41 Enzymatic rearrangement of sucrose to isomaltose. (From Lina et al., Food Chem. Toxicol., 40:375–381, 2002. With permission.)

Palmetto berries

Palmetto berries are obtained from Saw palmetto, an herbal product used to treat symptoms related to benign prostatic hyperplasia. Studies demonstrated the effectiveness of saw palmetto in reducing symptoms associated with benign prostatic hyperplasia (Ernt, 2002; Gordon and Shaughnessy, 2003) and lower urinary-tract symptoms (Wilt et al., 1998; Koch, 2001). The mechanism whereby saw palmetto improves urinary symptoms is unknown (Gerber et al., 2001). There are no known drug interactions with saw palmetto, with reported side effects extremely rare. A six-month study of forty-four men with benign prostatic hyperplasia with a Saw palmetto herbal by Veltri et al. (2002) found an alteration in DNA chromatin structure and organization of prostate epithelial cells. Goldman et al. (2001) reported inhibition of proliferation of a set of prostatic cell lines when dosed with Saw palmetto-berry extract (SPBE) for three days. Reduced cellular activity appeared to be related to decreased expression of COX-2 and possible changes in the expression of Bcl-2. Since an increase in COX-2 expression is associated with an increase in incidence of prostate cancer, its reduction by SPBE suggests its possible use against benign proprostatic hyperplasia and in prostate-cancer prevention. Talpur et al. (2003) showed whole berry and extracts of Saw palmetto influenced hyperplasia via androgen metabolism.

References

Ernst, E., The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John’s wort, ginseng, echinacea, saw palmetto, and kava, Ann. Intern. Med., 136:42–53, 2002.

Gerber, G.S., Kuznetsov, D., Johnson, B.C., and Burstein, J.D., Randomized, double-blind, placebocontrolled trial of saw palmetto in men with lower urinary tract symptoms, Urology, 58:960–964, 2001.

Goldmann, W.H., Sharma, A.L., Currier, S.J., Jonston, P.D., Rana, A., and Sharma, C.P., Saw palmetto berry extract inhibits cell growth and COX-2 expression in prostatic cancer cells, Cell Biol. Int., 25: 1117–1124, 2001.

Gordon, A.E. and Shaughnessy, A.F., Saw palmetto for prostate disorders, Am. Fam. Physician, 67:1281–1283, 2003.

Koch, E., Extracts from fruits of saw palmetto (Sabal serrulata) and roots of stinging nettle (Urtica dioica): Viable alternatives in the medical treatment of benign prostatic hyperplasia and associated lower urinary tracts symptoms, Planta Med., 67:489–500, 2001.

Talpur, N., Echard, B., Bagchi, D., Bagchi, M., and Preuss, H.G., Comparison of saw palmetto (extract and whole berry) and cernitin on prostate growth in rats, Mol. Cell Biochem., 250:21– 26, 2003.

Veltri, R.W., Marks, L.S., Miller, M.C., Bales, W.D., Fan, J., Macairan, M.L., Epstein, J.I., and Partin, A.W., Saw palmetto alters nuclear measurements reflecting DNA content in men with symptomatic BPH: Evidence for a possible molecular mechanism, Urology, 60:617–622, 2002.

Wilt, T.J., Ishani, A., Stark, G., MacDonald, R., Lau, J., and Mulrow, C., Saw palmetto extracts for treatment of benign prostatic hyperplasia: A systematic review, JAMA, 280:1504–1609, 1998.

Paprika (Capsicum annuum L.)

Carotenoids have been reported to play a role in the prevention of cancer. Oshima et al. (1997) showed that capsanthin, a major carotenoid in paprika (Capsicum annuum), was absorbed into the body following ingestion of paprika juice. In addition to capsanthin, 11-cis-capsanthin was also identified and could also be important to human health. Narisawa et al. (2000) reported that paprika juice rich in capsanthin (3.54 mg/100 mL) inhibited N-methylnitrosourea- induced colon carcinogenesis in F344 rats. Etoh and coworkers (2000) also reported the absorption of paprika carotenoids following ingestion of paprika juice. The red pigments in paprika, capsanthin, capsorubin, and capsanthin 3,6-epoxide, all possess 3-hydroxy-κ-end groups (Scheme P.42). The antitumor activity of isolated paprika carotenoids associated with these structures was demonstrated by Maoka and coworkers (2001) using an Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and an in vitro, two-stage carcinogenesis assay on mouse skin using 7,12-dimethylbenz[α]anthracene as an initiator and promoter. Strong, antitumor promoting activities were observed for capsanthin and related paprika carotenoids without any significant cytotoxicity to the Raji cells in this assay. Inhibitory activity increased with esterification of the hydroxyl groups with fatty acids, as evident by the increase in inhibitory activity ranging in the order of capsanthin>capsanthin 3′ ester> capsanthin diester>capsorubin diester. This was also evident for inhibition of TPA-induced tumor promotion by capsanthin, capsanthin 3,3″-diester, as shown in Figure P.71.

Structures of capsanthin and related paprika carotenoids. (From Maoka et al., Cancer Lett., 172:103–109, 2001. With permission.)

Sappanen and Csallany (2002) reported in vivo antioxidant effects in rats fed vitamin E-deficient diets supplemented with paprika carotenoids (0.5 and 1.0 percent) and β- carotene (1.0 percent) by the lower amount of secondary products from lipid peroxidation in the urine. While the addition of paprika carotenoids could not compensate for the role of vitamin E in normal growth and weight gain, these oxygenated carotenoids, or xanthophylls, were effective by their in vivo inhibition of lipid oxidation. Perez-Galvez et al. (2003) showed the availability of carotenoids from paprika oleoresin by the detection of considerable amounts of zeaxanthin, β-cryptoxantin, and β-carotene in the chylomicron fraction.

References

Etoh, H., Utsunomiya, Y., Konori, A., Murakami, Y., Oshima, S., and Inakuma, T., Carotenoids in human blood plasma after ingesting paprika juice, Biosci. Biotechnol. Biochem., 64:1096–1098, 2000.

Maoka, T., Michida, K., Kozuka, M., Ito, Y., Fujiwara, Y., Hashimoto, K., Enjo, F., Ogata, M., Nobukuni, Y., Tokuda, H., and Nishino, H., Cancer chemopreventive activity of carotenoids in the fruits of red paprika Capsicum annuum L., Cancer Lett., 172:103–109, 2001.

Narisawa, T., Fukaura, Y., Hasebe, M., Nomura, S., Oshima, S., and Inakuma, T., Prevention of N-methylnitrosourea- induced colon carcinogenesis in rats by oxygenated carotenoid capsanthin and capsanthin-rich paprika juice, Proc. Soc. Exp. Biol. Med., 224:116–122, 2000.

Oshima, S., Sakamoto, H., Ishiguro, Y., and Teraom, J., Accumulation and clearance of capsanthin in blood plasma after ingestion of paprika juice in men, J. Nutr., 127:1475–1479, 1997.

Parez-Galvez, M., Martin, H.D., Sies, H., and Stahl, W., Incorporation of carotenoids from paprika oleoresin into human chylomicrons, Br. J. Nutr., 89:787–793, 2003.

Seppanen, C.M. and Csallany, A.S., The effect of paprika carotenoids on in vivo lipid peroxidation measured by urinary excretion of secondary oxidation products, Nutr. Res., 22:1055–1065, 2002.

FIGURE P.71 Inhibition of TPA-induced tumor promotion by multiple applications of capsanthin, capsanthin 3′ ester, and capsanthin diester. All mice were initiated with DMBA (390 nmol) and promoted with TPA (1.7 nmol) twice weekly starting at one week after initiation. (A) Percentage of mice bearing papillomas; (B) Average number of papillomas per mouse. Control TPA alone; ( ■) TPA+85 nmol capsanthin; (▲), TPA + 85 nmol capsanthin 3′ ester; (×), TPA+85 nmol capsanthin 3,3′-diester. (From Maoka et al., Cancer Lett., 172:103–109, 2001. With permission.)

Parsley (Petroselinium crispum)

Parsley has a long tradition in folk medicine as a stomachic, carminative, emmenagogue, and abortifacient (Anderson et al., 1996; Robbers and Tyler, 1999; Tyler, 1993). As an herb, it is widely recognized as a diuretic, which could account for its hypotensive properties (Leung, 1980). The mechanism of its diuretic effect appears to be mediated through inhibition of the Na+ K+ pump that leads to a reduction in Na+ and K+ reabsorption, resulting in an osmotic water flow into the lumen and diuresis (Kreydiyyeh and Usta, 2002). Earlier work by Kreydiyyeh et al. (2001) confirmed the laxative role of parsley by its inhibition of sodium and subsequent water absorption through its inhibition of the Na+K+ pump, and by stimulating of the NaKCl transporter and increasing electrolyte and water secretion.

Yoshikawa et al. (2000) found the methanolic extract from the aerial parts of parsley had potent estrogenic activity. This was attributed to several flavone glycosides, including a new flavone glycoside, 6″-acetylapiin, together with a new monoterpene, petroside.

Manderfeld et al. (1997) demonstrated the antibacterial properties of parsley leaves. The photoactive furocoumarins extracted from the leaves inhibited human pathogens, E. coli and Lesteria monocytogenes, and the spoilage organisms, Erwinia carotovora and Listeria innocua. Flavones, apigenin, luteolin, and chrysoeriol, and flavonols, quercetin and isorhamnetin, isolated from illuminated parsley-cell suspension culture, increased the antioxidative capacity in the plasma of rats (Hempel et al., 1999). Parsley is one of the medicinal herbs used by diabetics in Turkey and is reported to reduce blood pressure (Tunali et al., 1999).

References

Anderson, L.A., Nevall, C.A., and Phillipson, J.D., Herbal Medicine/A Guide for Health-Care Professionals, The Pharmaceutical Press, London, 1996, pp. 203–204.

Hempel, J., Pforte, H., Raab, B., Engst, W., Bohm, H., and Jacobasch, Flavonols and flavones of parsley cell suspension culture change the antioxidative capacity of plasma in rats, Nahrung, 43:201–204, 1999.

Kreydiyyeh, S.I. and Usta, J., Diueretic effect and mechanism of action of parsley, J. Ethnopharmacol., 79:353–357, 2002.

Kreydiyyeh, S.I., Usta, J., Kaouk, A., and Al-Sadi, R., The mechanism underlying the laxative properties of parsley extract, Phytomedicine, 8:382–388, 2001.

Leung, A.Y., Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics, John Wusket & Sons, New York, 1980, p. 409.

Manderfeld, M.M., Schafer, H.W., Davidson, P.M., and Zottola, E.A., Isolation and identification of antimicrobial furocoumarins from parsley, J. Food Prot., 60:72–77, 1997.

Robbers, J.E. and Tyler, V.E., Tyler’s Herbs of Choice, The Therapeutic Use of Phytochemicals, Haworth Herbal Press, New York, 1999.

Tunali, T., Yarat, A., Yanardag, R., Ozcelik, F., Ozsoy, O., Ergenekon, G., and Emekeli, N., Effect of parsley (Petroselinum crispum) on the skin of STZ-induced diabetic rats, Phytother. Res., 13:138–141, 1999.

Tyler, V.E., The Honest Herbalist, third ed., Pharmaceutical Products Press, New York, London, Norwood, pp. 235–236, 1993.

Yoshikawa, M., Uemura, T., Shimoda, H., Kishi, A., Kawahara, Y., and Matsuda, H., Phytoestrogens from aerial part of Petroselinum crispum Mill, (parsley) and structures of 6″- acetylapiin and a new monoterpene glycoside, petroside, Chem. Pharm. Bull., 48: 1039–1044, 2000.

Palm oil

Palm oil, a yellowish, fatty oil obtained from the crushed nuts of the African palm (Elaeis guineensis), is used in the manufacture of soaps, chocolates, cosmetics, and candles. The oil contains 50 percent saturated fatty acids, 40 percent unsaturated fatty acids, and 10 percent polyunsaturated fatty acids but does not promote atherosclerosis and arterial thrombosis. The saturated to unsaturated fattyacid ratio of palm oil is close to one with oleic acid, predominantly at the sn2-position in the main triacylglycerols (Ong and Goh, 2002). Palm oil also contains a large amount of antioxidants, β-carotene, and vitamin E (Ebong et al., 1999). The fruit of palm also contains other components that could enhance the nutritional and health benefits. These include phytonutrients, such as sterols (sitosterol, stigmasterol, and campesterol), phospholipids, glycolipids, and squalene. In addition, it was recently reported that water-soluble, powerful antioxidants, phenolic acids, and flavonoids can be recovered from the palm oil mill effluent (Wattanapenpaiboon and Wahlqvist, 2003).

The benefits of palm oil to health include reduction in the risk of arterial thrombosis and atherosclerosis (Van Jaarsvels et al., 2002), inhibition of endogenous cholesterol biosynthesis, platelet aggregation, lowering of blood triglycerides (or reduced fat storage) as compared with polyunsaturated fat diets (Ong and Goh, 2002), retarding oxidation of low-density lipoproteins, promoting vascular relaxation (Abeywardena et al., 2002), and reduction in blood pressure. Lipolysis of palm-oil triacylglycerols containing oleic acid mainly at the sn-2 position and palmitic and stearic acids at sn 1 and 3 positions allows for the ready absorption of the 2-monoacylglycerols, while the saturated fatty acids are poorly absorbed (Ong and Goh, 2002). Unlike fresh palm oil, oxidized palm (resulting from processing for culinary purposes) induces an adverse lipid profile, reproductive toxicity, and toxicity of the kidney, lung, liver, and heart (Edem, 2002).

FIGURE P.72A Effect of pretreatment of palm oil on TPA-mediated epidermal ODC activity. Each value represents the mean DNA±SE of six animals, (a) Significantly different (p<0.001) compared with the acetone-treated control, (b) Significantly different (p<0.01) compared with the TPA-treated group, (c) Significantly different (p<0.001) compared with the TPA-treated group, (d) Significantly different (p <0.01) compared with the P.O. (D1)+TPA-treated group. P.O. (D1), significantly palm oil (100 L); P.O. (D2), palm oil (150 L). (From Kausar et al., Cancer Lett., 192:151–160, 2003. With permission.)

Red palm oil is a rich source of β-carotene, α-carotene, and tocotrienols (Ong and Goh, 2002). Solomon (1998) showed that β-carotene in red palm oil can be used as a supplement to restore and preserve vitamin A in school children. Radhika et al. (2003) reported red-palmoil supplementation significantly improved maternal and neonatal vitamin A status and reduced the prevalence of maternal anemia. The effect of palm-oil carotene supplementation was shown by Nesaretman et al. (2002) to modulate the immune system by increasing peripheral blood NK cells and B-lymphocytes and suppress the growth of MCF-7 human breastcancer cells. The antitumor properties of palm oil (P.O.) were examined by Kausar et al. (2003) against 12-O-tetradecanoyl-phorbol-13 - acetate (TPA)-induced skin tumorigenesis in Swiss albino mice. The antiskin-tumor effects of palm oil (P.O.) involved inhibition of ornithine decarboxylase (ODC) and [(3)H]thymidine incorporation, conventionally used markers for skin-tumor promotion and cutaneous oxidative stress (Figure P.72A, B).

FIGURE P.72B Effect of pretreatment of palm oil on TPA-mediated [³H]thymidine incorporation in epidermal. The data represent the percentage of the acetone-treated control value. The actual acetonetreated control value is 5.00±8.46 DPM/mg DNA. The TPA-treated control is 186±9.66 DPM/mg DNA. The values represent the mean±six animals, (a) Significantly different (p<0.001) compared with the acetone-treated control, (b) Different (p<0.05) when compared with the TPA-treated group, (c) Significantly different (p<0.01) compared with the TPA-treated group, (d) Significantly different (p< 0.05) when compared with the P.O.(D1)+TPA-treated group. P.O. (D1), palm oil (100 L); P.O. (D2), palm oil (150 L). (From Kausar et al., Cancer Lett., 192:151–160, 2003. With permission.)

Other studies showed the tocotrienol-rich fraction (TRF) of palm oil inhibited cell growth and induced apoptosis in both preneoplastic and neoplastic cells. Argawal et al. (2004) suggested that the mechanism of TRF-induced apoptosis in colon carcinoma cells was mediated by p53 signaling network independently of cellcycle association.

References

Abeywardena, M., Runnie, I., Nizar, M., Momamed, S. and Head, R., Polyphenol-enriched extract from oil palm fronds (Elates guineensis) promotes vascular relaxation via endothelium-dependent mechanisms, Asian Pacific J. Clin Nutr., 11 (Suppl.): S467– S472, 2002.

Argawal, M.K., Argawal, M.L., Athar, M., and Gupta, S., Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association, Cell Cycle, 3:205–211, 2004.

Cottrell, R.C., Introduction: Nutritional aspects of palm oil, Am. J. Clin. Nutr., 53:9895–10095, 1991.

Ebong, P.E., Owu, D.U., and Isong, E.U., Influence of palm oil (Elaesis guineensis) on health, Plant Foods Hum. Nutr., 53:209–222, 1999.

Edem, D.O., Palm oil: Biochemical, physiological, nutritional, hematological, and toxicological aspects: A review, Plant Foods Hum. Nutr., 57:319–341, 2002.

Kausar, H., Bhasin, G., Zargar, M.A., and Athar, M., Palm oil alleviates 12-O-tetradecanoylphorbol- 13-acetate-induced tumor promotion response in murine skin, Cancer Lett., 192:151– 160, 2003.

Nesaretnam, K., Radhakrishnan, A., Selvaduray, K.R., Reimann, K., Pailoor, J., Razak, G., Mahmood, M.M., and Dahliwal, J.S., Effect of palm oil carotene on breast cancer tumorigenicity in nude mice, Lipids, 37:557–560, 2002.

Ong, A.S.H. and Goh, S.H., Palm oil: A healthful and cost-effective dietary component, Food Nutr. Bull., 23:11–22, 2002.

Radhika, M.S., Bhaskaram, P., Balakrishna, N., and Ramalakshmi, B.A., Red palm oil supplementation: A feasible diet-based approach to improve vitamin A status of pregnant women and their infants, Food Nutr. Bull., 24:208–217, 2003.

Solomons, N.W., Plant sources of vitamin A and human nutrition: Red palm oil does the job, Nutr. Rev., 56:309–311, 1998.

Van Jaarsveld, P.J., Smuts, C.M., and Benade, A.J.S., Effect of palm olein in a moderate-fat diet on plasma lipoprotein profile and aortic atherosclerosis in non-human primates, Asia Pac. J. Clin. Nutr., 11(Suppl. 7):S424–S432, 2002.

Wattanapenpaiboon, N. and Wahlqvist, M.L., Phytonutrient deficiency: the place of palm fruit, Asia Pac. J. Clin. Nutr., 12:363–368, 2003.

Pau d’arco

Tabebuia trees are native to the tropical rain forests in Central and South America. A commercial product, lapacho, obtained from its bark, is also known as Pau d’arco, Taheebo, and ipe-roxo. The main species used in folk medicine is Tabebuia impetiginosa. Pau d’arco has been used for many years as an anticancer, antifungal, antibacterial, and antiinflammatory drug (Zani et al., 1991). A number of naphthoquinones identified in Tabebuia included lapachol and dehydro-α-lapachol, together with a- and β-lapachones (Burnett and Thomson, 1967; Steinert et al., 1995).

Lapachol was reported to be effective against a number of tumors, as well as exhibited antiiflammatory activity (Subramanian et al., 1998; Almeida et al., 1990). The most extensively studied component in the heartwood of T. impetiginosa is β-lapachone, whose antitumor properties appear to involve the production of reactive-oxygen species (Portela and Stoppani, 1996). In addition, β-lapachone has been found to induce apoptosis in tumor cells (Chau et al., 1998), as well as topoisomerase II-mediated DNA cleavage (Frydman et al., 1997). Further work by Muller et al. (1999) identified a number of lapacho compounds that were potent inhibitors of human keratinocyte growth of which naphtho[2,3-b]furan-4.9-diones were considered the most effective ingredients for treating psoriasis.

Anesini and Perez (1993) screened 132 extracts from Argentine folk-medicinal plants for antimicrobial activity using a penicillinresistant strain of Staphyloccocus aureus, Escherichia coli, and Aspergillus niger. Of these, Tabebuia impetiginosa produced some of the more active extracts against these organisms.

Koyama et al. (2000) isolated two cyclopenetene dialdehydes from the bark of Tabebuia. They were characterized as 2-formyl-5-(4′-methoxybenzoyloxy)-3-methyl-2-cyclopentene-1-acetaldehyde (1) and 2-formyl-5-(3′,4′-dimethoxybenzoyloxy)-3-methyl-2-cyclopentene-1-acetaldehyde (2). Both compounds exhibited potent anti-inflammatory activity against 12-O-tetradecanoylphorbol (TPA)-activated human PMN compared to alkylated benzoic acids (Figure P.73).

Structure of lapacho compounds. (From Muller et al., J. Nat. Prod., 62:1134–1136, 1999.)

FIGURE P.73 Anti-inflammatory activities of 1 and 2 in the TPA-activated human PMN compared with alkylated benzoic acids, ○ 1; ● 2; □ 4-methoxybenzoic acid; ■ 3,4-dimethoxybenzoic acid. (From Koyama et al., Phytochemistry, 53:869–872, 2000. With permission.)

The major volatile constituents of T. impetiginosa with antioxidant activity were shown by Park et al. (2003) to be 4-methoxybenzaldehyde, 4-methoxyphenol, 5-allyl-1,2,3-trimethoxybenzene (elimicin), 1-methoxy-4-(1E)-1-propenylbenzene (transanaethole), and 4-methoxybenzyl alcohol. These volatiles were found to be as effective as α-tocopherol and BHT in their ability to inhibit the formation of conjugated diene hydroperoxides from methyl linoleate and the oxidation of hexanal.

Warashina et al. (2004) recently reported the presence of 19 glycosides in the bark of Tabebuia impetiginosa. These included four iridoid glycosides, two lignan glycosides, two isocoumarin glycosides, three phenylethanoid glyosides, and eight phenolic glycosides.

References

Anesini, C. and Perez, C., Screening of plants in Argentine folk medicine for antimicrobial activity, J. Ethnopharmacol., 39:119–128, 1993.

Burnett, A.R. and Thomson, R.H., Naturally occurring quinones, X. Quinonoid constituents of Tabebuia avellanedae, J. Chem. Soc., C:2100–2104, 1967.

Chau, Y.-P., Shiah, S.-C, Don, M.-J., and Kuo, M.L., Involvement of hydrogen peroxide in topoisomerase inhibitor β-lapachone-induced apoptosis and differentiation in human leukemia cells, Free Rad. Biol. Med., 24:660–770, 1998.

de Almeida, E.R., da Silva Filho, A.A., dos Santos, E.R., and Lopes, C.A.C., Anti-inflammatory action of lapachol, J. Ethnopharmacol., 29:239–241, 1990.

Frydman, B., Marton, L.J., Sun, J.S., Neder, K., Witiak, D.T., Liu, A.A., Wang, H.M., Mao, Y., Wu, H.Y., Sanders, M.M., and Liu, L.F., Induction of DNA topoisomerase II-mediated DNA cleavage by β-lapachone and related naphthoquinones, Cancer Res., 57:620–627, 1997.

Koyama, J., Morita, I., Tagahara, K., and Hirai, K., Cyclopentene dialdehydes from Tabebuia impetiginosa, Phytochemistry, 53:869–872, 2000.

Muller, K., Sellmer, A., and Wiegrebe, W., Potential antipsoriatic agents: Lapacho compounds as potent inhibitors of HaCaT cell growth, J. Nat. Prod., 62: 1134–1136, 1999.

Park, B.S., Lee, K.G., Shibamoto, T., Lee, S.E., and Takeoka, G.R., Antioxidant activity and characterization of volatile constituents of Taheebo (Tabebuia impetiginosa Martinus ex DC), J. Agric. Food Chem., 51:295–300, 2003.

Portela, M.P.M. and Stopani, A.O.M., Redox cycling of β-lapachone and related Onaphthoquinones in the presence of dihydrolipoamide and oxygen, Biochem. Pharmacol., 51:275–283, 1996.

Steinert, J., Khalaf, H., and Rimpler, M., HPLC separation and determination of naphtho[2,3- b]furan4,9-diones and related compounds in extracts of Tabebuia avellanedae (Bignoniaceae), J. Chromatogr. A, 693:281–287, 1995.

Subramanian, S., Ferreira, M.M.C., and Trsic, M., A structure-activity relationship study of lapachol and some derivatives of 1,4-naphthoquinones against carcinosarcoma walker 256, Struct. Chem., 9:47–57, 1998.

Warashina, T., Nagatani, Y., and Noro, T., Constituents from the bark of Tabebuia impetiginosa, Phytochemistry, 65:2003–2011, 2004.

Zani, C.L., de Oliviera, A.B., and de Oliviera, G.G., Furanonaphthoquinones from Tabebuia ochracea, Phytochemistry, 30:2379–2381, 1991.

Pears

Pears are a good source of vitamin C (3.8 mg/100 g), vitamin K (4.5 mg/100 g), and dietary fiber (4 g/100 g). The average concentration of phenolic compounds in pears harvested at commercial maturity stage is 3.7 g/kg fresh pulp. The predominant phenolics are procyanidins (96 percent), together with hydroxycinnamic acids (2 percent), arbutin (0.8 percent), and catechins (0.7 percent). Sun-drying causes a decrease of 64 percent (on a dry-pulp basis) in the total amount of native phenolic compounds (Fereira et al., 2002). A comparison of different pear cultivars showed a wide range in both phenolic content (272 to 475 mg of CtE/100 g fresh fruit) and in vitro antioxidant activity in the order of Forelle>Taylor>Peckham>Conference. A later study by Sanchez et al. (2003) compared six pear cultivars and found most of the phenolics were located in the peel, ranging from 1235 to 2005 mg/kg compared to 28–81 mg/kg for the corresponding flesh. Vitamin C was also higher in the peels, accounting for 116 to 228 mg/kg compared to 28–53 mg/kg in the flesh. A correlation of r= 0.46 was evident between antioxidant capacity and chlorogenic acid, with vitamin C only making a small contribution. Tanrioven and Eksi (2004) recently showed pear juice from seven different varieties ranged in total polyphenolics from 196 to 457 mg/L. Chlorogenic acid, the main phenolic, accounted for 73.1 to 249 mg/L, followed by epicatechin, which ranged from 11.9 to 81.3. The two remaining polyphnols were caffeic and p-coumaric acids, each accounting for 2.4–11.4 and 0.0–3.0 mg/L, respectively.

Leontowicz et al. (2002) examined the bioactive compounds in apples, peaches, and pears and their effect on lipids and antioxidant capacity in rats. Diets supplemented with apples and, to a lesser extent, with peaches and pears, improved lipid metabolism and plasma-antioxidant potential. They attributed the antioxidant properties of apples and pears to their polyphenols, phenolic acids, and flavonoids, with the peels being significantly higher (p<0.05) than the pulp. Diets supplemented with fruit peels with added cholesterol exercised a significantly positive influence on rat plasma lipids, with pear peel being less effective than apple peel. The ability to counteract hypercholesterolemia and oxidative stress was consistent with a previous study using lyophilized apple by Aprikan et al. (2002). Because peels were much richer in polyphenols, the washed whole fruit was recommended.

References

Aprikian, O., Busserolles, J., Manach, C., Mazur, A., Morand, C., Davicco, M.J., Besson, C., Rayssiguier, Y., Remesy, C., and Demigne, C., Lyophilized apple counteracts the development of hypercholesterolemia, oxidative stress, and renal dysfunction in Zucker rats, J. Nutr., 132:1969–1976, 2002.

Fereira, D., Guyot, S., Marnet, N., Delgadillo, I., Renard, C.M.G.C., and Coimbra, M.A., Composition of phenolic compounds in a Portuguese pear (Pyrus communis L. var. S. Bartolomeu) and changes after sun-drying, J. Agric. Food Chem., 50:4537–4544, 2002.

Leontowicz, H., Gorinstein, S., Lojek, A., Leontowicz, M., Ciz, M., Soliva-Fortuny, R., Park, Y.S., Jung, S.T., Trakhtenberg, S., and Martin-Belloso, O., Comparative content of some bioactive compounds in apples, peaches and pears and their influence on lipids and antioxidant capacity in rats, J. Nutr. Biochem., 13:603–610, 2002.

Sanchez, A.C.G., Gil-Izquierdo, A.G., and Gil, M.I., Comparative study of six pear cultivars in terms of their phenolic and vitamin C contents and antioxidant capacity, J. Sci. Food Agric., 83:995–1003, 2003.

Tanrioven, D. and Eksi, A., Phenolic compounds in pear juice from different cultivars, Food Chem., 93: 89–93, 2005.

Pectin

Pectin, the main component of primary plant cell walls of all land plants, encompasses a range of galacturonic acid-rich polysaccharides. Three major pectic poly saccharides, homogalacturonan (HGA), rhamnogalacturonan-I (RG-I), and rhamnogalaturonan-II (RG-II), are present in all primary cell walls, together with cellulose, hemicellulose, and protein (Perez et al., 2003). The “canonical” primary structure of pectins is depicted in Scheme P.42. Pectin is used extensively in the food, pharmaceuticals, and related industries. The importance of pectin is related to its ability to form a gel in the presence of Ca²⁺ ions or a solute at low pH (Thakur et al., 1997).

The quality of fibrin networks and the concentration of fibrinogen are both thought to contribute to increasing the risk of cardiovascular disease. Veldman et al. (1999) showed pectin influenced the fibrin-network architecture in hypercholesterolemic men without causing any changes in fibrinogen concentration. The beneficial effects of pectin appeared to be mediated by acetate as it is fermented in the gastrointestinal tract to acetate, proprionate, and butyrate. Only acetate, however, reaches circulation in humans beyond the liver.

Vergara-Jimeneza et al. (1999) demonstrated that pectin reversed hyperlipidemia associated with high-fat sucrose diets and had a potential antioxidant effect on circulating LDL. The protective effect of pectin on cardiovascular disease was shown by Park and coworkers (2000) to be due to an increase in fecal excretion of neutral sterols and hepatic microsomal fluidity. However, pectin increased risk factors for colon cancer by increasing the production of secondary bile acids and short-chain fatty acids in the colon. Rats fed low-molecular-weight pectin were found by Grizard et al. (2001) to significantly decrease triacylglycerols, total cholesterol, and insulin concentrations without changing postprandial blood-glucose levels.

SCHEME P.42 Schematic representation of the “canonical” primary structure of pectins. For the sake of simplicity, their schematic representations of HGA, RG-I, and RG-II are given, assuming that these three domains are covalently linked, although this point is not firmly established. (From Perez et al., Biochimie, 85:109–121, 2003. With permission.)

Pectins also activate in vitro macrophages to be cytotoxic against tumor cells and microbial infections. Modifying citrus pectin, by enzymatic treatment to changes to the molecular structure of the long pectin chain, also inhibited metastases in animals with prostate cancer. Spontaneous lung metastases were also reduced by 60 percent if rats consumed 1 percent citrus pectin in their diets. Hayashi et al. (2000) reported that a pH-modified citrus pectin (MCP) significantly reduced the tumor size of colon-25 solid tumor implants in balb c mice. Rats receiving a low dose of (0.8 mg/mL) MCP produced a 38 percent (p<0.02) decrease in tumor size compared to an impressive 70 percent (p<0.001) reduction when animals were maintained on a high-dose (1.6 mg/mL) of MCP.

New developments with pectin-based formulations, particularly in the area of colon-specific drug-delivery systems, found that pectin showed great promise in engineering drugdelivery systems for oral drug delivery (Liu et al., 2003). Recent work by Liu et al. (2004) showed that composite matrices of pec-tin/poly(lactide-co-glycolide) had great potential for biomedical applications.

References

Grizard, D., Dalle, M., and Barthomeuf, C., Changes in insulin and corticosterone levels may partly mediate the hypolipidemic effect of guar gum and low-molecular weight pectin in rats, Nutr. Res., 21:1185– 1190, 2001.

Hayashi, A., Gillen, A.C., and Lott, J.R., Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice, Altern. Med. Rev., 5:546–552, 2000.

Hurd, L., Modified citrus pectin enhances the immune system, Total Health, 21:0274–6743, 1999.

Liu, L.S., Fishman, M.L., Kost, J., and Hicks, K.B., Pectin based systems for colon-specific drug delivery via oral route, Biomaterials, 24:3333–3343, 2003.

Liu, L.S., Won, Y.J., Cooke, P.H., Coffin, D.R., Fishman, M.L., Hicks, K.B., and Ma, P.X., Pectin/poly(lactide-co-glycolide) composite matrices for biomedical applications, Biomaterials, 25:3201–3210, 2004.

Park, H.S., Choi, J.S., and Kim, K.H., Docosahexaenoic acid-rich fish oil and pectin have a hypolipidemic effect, but pectin increases risk factor for colon cancer in rats, Nutr. Res., 20:1783–1794, 2000.

Perez, S., Rodriguez-Carvajal, M.A., and Doco, T., A complex plant cell wall polysaccharide: Rhamnogalacturonan II, a structure in quest of a function, Biochimie, 85:109–121, 2003.

Thakur, B.R., Singh, R.K., and Handa, A.K., Chemistry and uses of pectin, CRC Rev. Food Sci. Nutr., 37:47–73, 1997.

Veldman, F.J., Nair, C.H., Vorster, H.H., Vermaak, W.J.H., Jerling, J.C., Oosthuizen, W., and Venter, C.S., Possible mechanisms through which dietary pectin influences fibrin network architecture in hypercholesterolaemic subjects, Thrombosis Res., 93:253–264, 1999.

Vergara-Jimeneza, M., Furra, H., and Fernandeza, M.L., Pectin and psyllium decrease the susceptibility of LDL to oxidation in guinea pigs, J. Nutr. Biochem., 10:118–124, 1999.

Peony

Peonies, herbaceous cultivars of Paeoniae alba Radix (red peony root), the dried root of Paeoniae lactiflora Pallas or Paeoniae veitchii Lynch, originated in China more than 2,000 years ago. The root extract of peony was shown by Sakai et al. (1990) to inhibit the mutagenicity of benzo[a]pyrene-(B[a])p metabolites. Tsuda et al. (1997) found one of the bioactives in peony root extract (Paeoniae radix), gallotannin, partially protected neuron damage in the hippocampus of 7-week-old Wistar rats induced by the cobalt focus epilepsy model, while paeoniflorin, a second bioactive, had no effect. However, when both bioactives were combined, they provided complete protection, similar to the whole peony-root extract. Treatment with paeoniflorin was shown by Tabata et al. (2000) to reverse the suppressive effects of scopolamine and prenzepine (muscarinic receptor-antagonists) on long-term potentiation. Tabata et al. (2001) also found paeoniflorin ameliorated memory disruption mediated by the adenosine A1 receptor, which had a beneficial effect on learning and memory impairment in rodents.

The active principal of peony roots that lowered total and LDL cholesterol was identified by Shibata et al. (1963) as paeoniflorin. This water-soluble bioactive is pharmacologically active as an anti-inflammatory and antiallergic (Yamahara et al., 1982), antihyperglycemic (Hsu et al., 1997), and analgesic (Sugishita et al., 1984). More recent studies showed additional pharmacological effects, including antithrombosis (Ye et al., 2001), antihypotension (Cheng et al., 1999), and enhanced glucose uptake (Tang et al., 2003).

Paeoniflorin. (From He et al., J. Nat. Prod., 62:1134–1136, 1999. With permission.)

Yang et al. (2004) recently isolated paeoniflorin from the methanol extract of Paeonia lactiflora and examined its effect as an antihyperlipidemic agent. When 200 and 400 mg/kg of paeoniflorin were fed to experimentally induced hyperlipidemic adult male Wistar rats, plasma total-cholesterol levels were lowered significantly by 19.1 percent and 28.7 percent, respectively, in a dose-dependent manner. Under the same conditions, lovastatin, at a dose of 10 mg/kg, reduced plasma total cholesterol by 25.8 percent. Marked decreases in plasma triglycerides and LDL levels of 51.4 percent and 59.3 percent and 69.3 percent and 80.5 percent were also observed for the two doses of paeoniflorin, respectively. In contrast to lovastatin, which lowered HDL very slightly, paeoniflorin increased HDL by 14.9 percent and 6.3 percent for the two doses, respectively.

Chen et al. (1999, 2002) examined the pharmacokinetics of paeoniflorin in normal, healthy animals, while Ye and coworkers (2004) studied the effect of disease state on its pharmacokinetics. Using rats suffering from cerebral ischemia-reperfusion, they found marked differences in the pharmacokinetics of paeoniflorin between normal and diseased animals. For example, elimination of paeoniflorin slowed down in the ischemic-reperfusion rats, pointing to its accumulation in the pathological state. This information will ensure greater safety and efficacy when using paeoniflorin in clinical applications.

References

Chen, L.C., Lee, M.H., Chou, M.H., Lin, M.F., and Yang, L.L., Pharmacokinetic study of paeoniflorin in mice after oral administration of Paeoniae Radix extract, J. Chromatogr. B, 735:33–40, 1999.

Chen, L.C., Chou, M.H., Lin, M.F., and Yang, L.L., Pharmacokinetics of paeoniflorin after oral administration of Shao-yao Gan-chao Tang in mice, Jpn. J. Pharmacol., 88:250–255, 2002.

Cheng, J.T., Wang, C.J., and Hsu, F.L., Paeoniflorin reverses guanethidine-induced hypotension via activation of central adenosine A1 receptors in Wistar rats, Clin. Exp. Pharmacol. Physiol., 26:815–816, 1999.

He, X., Xing, D., Ding, Y., Li, Y., Xu, Y., and Du, L., Effects of cerebral ischemia-reperfusion on pharmacokinetic fate of paeoniflorin after intravenous administration of Paeoniae Radix extract in rats, J. Ethnopharmacol., 94:339–344, 2004.

Hsu, F.L., Lai, C.W., and Cheng, J.T., Antihyperglycemic effects of paeoniflorin and 8- debenzoylpaeoniflorin, glucosides from the root of Paeonia lactiflora, Planta Med., 63:323– 325, 1997.

Sakai, Y., Nagase, H., Ose, Y., Kito, H., Sato, T., Kawai, M., and Mizuno, M., Inhibitory action of peony root on the mutagenicity of benz[a]pyrene, Mutat. Res. Lett., 244:129–134, 1990.

Shibata, S., Nakahara, M., and Aimi, N., Studies on the constituents of Japanese and Chinese crude drugs, VIII. Paeoniflorin, a glucoside of Chinese peony root (1), Chem. Pharma. Bull., 11:372– 378, 1963.

Sugishita, S., Amagaya, S., and Ogihara, Y., Studies on the combination of Glycyrrhizal Radix in Shakuyakukanzo-To, J. Pharmacobio-dynamics, 7:427–435, 1984.

Tabata, K., Matsumoto, K., Murakami, Y., and Watanabe, H., Ameliorative effects of paeoniflorin, a major constituent of peony root, on adenosine A1 receptor-mediated impairment of passive avoidance performance and long-term potentiation in the hippocampus, Biol. Pharm. Bull., 24:496–500, 2001.

Tabata, K., Matsumoto, K., and Watanabe, H., Paeoniflorin, a major constituent of peony root, reverses muscarinic M1-receptor antagonist-induced suppression of long-term potentiation in the rat hippocampal slice, Jpn. J. Pharmacol., 83:25–30, 2000.

Tsuda, T., Sugaya, A., Oghuchi, H., Kishida, N., and Sugaya, E., Protective effects of peony root extract and its components on neuron damage in the hippocampus induced by cobalt focus epilepsy model, Exp. Neurol., 146:518–525, 1997.

Yamahara, J., Yamada, T., Kimura, H., Sawada, T., and Fujimura, H., Biologically active principles of crude drugs, II. Anti-allergic principles in “Shoseiryu-To” anti-inflammatory properties of paeoniflorin and its derivatives, J. Pharmaco-biodynamics, 5:921–929, 1982.

Yang, H.O., Ko, W.K., Kim, J.Y., and Ro, H.S., Paeoniflorin: An antihyperlipidemic agent from Paeonia lactiflora, Fitoterapia, 75:45–49, 2004.

Ye, J., Daun, H., Yang, X., Yan, W., and Zheng, X, Anti-thrombosis effect of paeoniflorin: Evaluated in a photochemical reaction thrombosis model in vivo, Planta Med., 67:766–767, 2001.

Peppermint (Mentha piperita)

Peppermint is a very popular herb with a unique flavor. The oil from peppermint is currently used in cosmetic formulations as a fragrance component. Both peppermint and peppermint oil have psychoactive properties and are believed to be effective for treating nervous disorders and mental fatigue (Tisserand, 1993). The oil is composed primarily of menthol and menthone. Other possible constituents include pulegone, menthofuran, and limone. Because of the toxicity of pulegone, this constituent is limited to < or=1 percent (Nair et al., 2001). Other microelements and macroelements measured in peppermint were As, Cd, Cu, Fe, Mg, Pb, and Zn (Fijalek et al., 2003). Peppermints also contain antioxidants (i.e., >75 mmol/100 g) (Dragland et al., 2003). They are usually taken after a meal because of their ability to reduce indigestion and colonic spasms by reducing the gastrocolic reflex. It was recently shown that peppermint has a potential role in the management of certain procedures, such as colonoscopy (Spirling and Daniels, 2001) and during upper endoscopy (Hiki et al., 2003). The oil is harmless and acts locally in the stomach and duodenum to produce smooth-muscle relaxation in healthy volunteers (Micklefield et al., 2003).

Adapted from Hall, Eur. J. Pharmacol., 506:9–16, 2004.

May and coworkers (2003) demonstrated good tolerability and a favorable risk-benefit ratio of a fixed combination of 90 mg peppermint oil and 50 mg caraway oil for the treatment of functional dyspepsia. Pittler and Ernst (1998) reviewed clinical trials using peppermint extracts and were unable to establish beyond a reasonable doubt the efficacy of peppermint as a symptomatic treatment for irritable bowel syndrome.

A recent study by Norrish and Dwyer (2005) showed peppermint diminished daytime sleepiness, normally associated with sitting in a dark room. The invigorating effects of peppermint oil could enable people to remain awake, such as during the night shift.

References

Dragland, S., Senoo, H., Wake, K., Holte, K., and Blomhoff, R., Several culinary and medicinal herbs are important sources of dietary antioxidants, J. Nutr., 133:1286–1290, 2003.

Fijalek, Z., Soltyk, K., Lozak, A., Kominek, A., and Ostapczuk, P., Determination of some micro-and macroelements made from peppermint and nettle leaves, Pharmazie, 58:480–482, 2003.

Hall, A.C., Turcotte, C.M., Betts, B.A., Yeung, W-Y., Agyeman, A.S. and Burk, L.A., Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids, Eur. J. Pharmacol., 506:9–16, 2004.

Hiki, N., Kurosaka, H., Tatsutomi, Y., Shimoyama, S., Tsuji, E., Kojima, J., Shimizu, N., Ono, H., Hirooka, T., Noguchi, C., Mafune, K., and Kaminishi, M., Peppermint oil reduces gastric spasm during upper endoscopy: A randomized, double-blind, double-dummy controlled trial, Gastrointest. Endosc., 57:475–482, 2003.

May, B., Funk, P., and Schneider, B., Fixed peppermint oil/caraway oil combination in functional dyspepsia-efficacy unaffected by H. pylori status, Aliment Pharmacol. Ther., 17:975–976, 2003.

Micklefield, G., Jung, O., Greving, I., and May, B., Effects of intraduodenal application of peppermint oil (WS® 1340) and caraway oil (WS® 1520) on gastroduodenal motility in healthy volunteers, Phytother. Res., 17:135–140, 2003.

Nair, B., Final report on the safety assessment of Mentha piperita (peppermint) oil, Mentha piperita (peppermint) leaf extract, Mentha piperita (peppermint) leaf, and Mentha piperita (peppermint) leaf water, Health, 121(Suppl. 3):61–73, 2001.

Norrish, M.I. and Dwyer, K.L., Preliminary investigation of the effect of peppermint oil as an objective measure of daytime sleepiness, Int. J. Psychophysiol., 55:291–298, 2005.

Pittler, M.H. and Ernst, E., Peppermint oil for irritable bowel syndrome: A critical review and metaanalysis, Am. J. Gastroenterol., 93:1131–1135, 1998.

Spirling, L.I. and Daniels, I.R., Botanical perspectives on health peppermint: More than just an after-dinner mint, J.R. Soc. Health, 121:62–63, 2001.

Tisserand, R., The Art of Aromatherapy, C.W.Daniel, Essex, U.K., 1999.

Peppers

see also Capsaicin, Chili peppers, and Red peppers Peppers (Capsicum annum L.) are good sources of provitamin carotenoids, α-carotene, β-carotene, and cryptozanthin and a wide array of neutral and acidic phenolic compounds. As peppers mature, the concentrations of these carotenoids increase, together with phenolic acids, capxanthin, and zeaxanthin (Howard et al., 2000). Lutein, on the other was shown to decline. Peppers contain high levels of L-ascorbic acid and carotenoids at maturity, contributing 124–338 percent of the RDA for vitamin C and 0.33–336 RE/100 g provitamin A carotenoids. Peppers also contain oxygenated carotenoids or xanthophylls, which do not possess vitamin A activity but are still effective free-radical scavengers and may help to prevent age-related macular degeneration and cataracts.

Jimeneze et al. (2003) reported that antioxidant capacity and ascorbate content were higher in red peppers than green peppers and that storage increased ascorbate content in both green and red fruits.

The concentration of capsaicinoids in fresh peppers was variable, depending on the relative pungency of the pepper type and geographical origin of the pepper (Reilly et al., 2001). The health-related properties are discussed under capsaicin. Fresh, whole, homogenized peppers have characteristic volatile components, including hydrocarbons, terpenes, alcohols, phenols, ethers, aldehydes, ketones, esters, pyrroles, pyrazines, and sulfurous compounds (Oruna-Concha et al., 1998).

References

Howard, L.R., Talcott, S.T., Brenes, C.H., and Villalon, B., Changes in phytochemical and antioxidant activity of selected pepper cultivars (Capsicum species) as influenced by maturity, J. Agric. Food Chem., 48:1713–1720, 2000.

Jimenez, A., Romojaro, F., Gomez, J.M., Llanos, M.R., and Sevilla, F., Antioxidant systems and their relationship with the response of pepper fruits to storage at 20 degrees C, J. Agric. Food Chem., 51: 6293–6299, 2003.

Oruna-Concha, M.J., Lopez-Hernandez, J., Simal-Lozano, J.A., Simal-Gandara, J., Gonzalez- Castro, M.J., and de la Cruz Garcia, C., Determination of volatile components in fresh, frozen, and freezedried Padron-type peppers by gas chromatographymass spectrometry using dynamic headspace sampling and microwave desorption, J. Chromatogr. Sci., 36:583–588, 1998.

Reilly, C.A., Crouch, D.J., and Yost, G.S., Quantitative analysis of capsaicinoids in fresh peppers, ole-oresin capsicum and pepper spray products, Forensic. Sci., 46:502–509, 2001.

Peptides

see Biopeptides

Perilla

Perilla (Perrilla frutescens L.), a common annual weed in the Eastern United States, is a commercial crop in Asia. It is a member of the mint family, and its leaves are used for medicinal purposes. Asian herbalists prescribe perilla for cough and lung afflictions, influenza prevention, etc. Volatile components in perilla oil include an aldehyde chemotype that is the basis of Japanese Ao-shiso, a medicine with an agreeable fragrance (Koezuka et al., 1986). In addition, a perilla ketone was shown to be a very effective laxative without causing diarrhea in laboratory mice (Koezuka et al., 1985). The leaves of perilla have been used for centuries in Chinese medicine for treating a variety of diseases. Chen and coworkers (2003) identified three bioactive triterpenes in perilla leaves as tormentic acid (TA), oleanolic acid (OA), and ursolic acid (UA).

Structure of perilla leaf bioactive triterpenes. (From Chen et al., J. Pharm. Biomed. Anal., 32:1175–1179, 2003. With permission.)

TA: R1=R₃=OH, R₂=CH₃, R₄=H
OA: R1=R₂=R₃=H, R₄=CH₃
UA: R₁=R₃=R₄=H, R₂=CH₃

The major poly phenol in perilla-leaf extract, rosmarinic acid, was shown by Osakabe et al. (2002) to reduce liver damage induced by lipopolysaccharides and D-galactosamine by scavenging or reducing the activities of super-oxide or peroxynitrite.

Perilla-seed oil is used extensively for cooking in Asian countries. It is one of the richest sources of alpha linolenic acid, reported to prevent atherosclerosis and chemically induced cancer, as well as improves immune and mental function (Yamamoto et al., 1987; Shoda et al., 1995; Sadi et al, 1996; Onogi et al., 1996). The hypolipidemic effect of perilla oil was recently demonstrated by Kim et al. (2004), who showed that feeding rats a diet rich in perilla oil suppressed hepatic fatty-acid synthase, which significantly lowered plasma triacylglycerol levels.

Rosmarinic acid. (From Osakabe et al., Free Rad. Biol. Med., 33:798– 806, 2002. With permission.)

References

Chen, J.H., Xia, Z.H., and Tan, R.X., High-performance liquid chromatographic analysis of bioactive triterpenes in Perilla frutescens, J. Pharm. Biomed. Anal., 32:1175–1179, 2003.

Kim, H.-K., Choi, S., and Choi, H., Suppression of hepatic fatty acid synthase by feeding a-linolenic acid rich perilla oil lowers plasma triacylglycerol level in rats, J. Nutr. Biochem., 15:485–492, 2004.

Koezuka, L.A., Honda, G., and Tabata, M., An intestinal propulsion promoting substance from Perilla frutescens and its mechanism of action, Planta Med., 39:228–231, 1985.

Koezuka, L.A., Honda, G., and Tabata, M., Genetic control of the chemical composition of volatile oils in Perilla frutescens, Phytochemistry, 25:2085–2087, 1986.

Onogi, N., Okuno, M., Komaki, C., Marikawi, H., Kawamori, T., Tanaka, T., Mori, H., and Muto, Y., Suppressing effect of perilla oil on azoxymethaneinduced foci of colonic aberrant crypts in rats, Carcinogenesis, 17:1291–1296, 1996.

Osakabe, N., Yasuda, A., Natsume, M., Sanbong, C., Kato, Y., Osawa, T., and Yoshikawa, T., Rosmarinic acid, a major polyphenolic component of Perilla frutescens reduces lipopolysaccharide (LPS)-induced liver injury in D-galactosamine (D-GalN)-sensitized mice, Free Rad. Biol. Med., 33:798–806, 2002.

Sadi, A.M., Toda, T., Oku, H., and Hokama, S., Dietary effects of corn oil, oleic acid, perilla oil, and primrose oil on plasma and hepatic lipid level and therosclerosis in Japanese quail, Exp. Anim., 45:55–62, 1996.

Shoda, R., Matsueda, K., Yamato, S., and Umeda, N., Therapeutic efficacy of n-3 polyunsaturated fatty acid in experimental Crohn’s disease, J. Gastroenterol., 30(Suppl. 8):98–101, 1995.

Yamamoto, N., Hashimoto, A, Takemoto, Y., Akuyama, H., Nomura, M., Kitajima, R., Togashi, T., and Tamai, Y., Effects of dietary α-linolenate/linoleate balance on lipid components and learning ability of rats, J. Lipid Res., 29:1013–1021, 1988.

Perillyl alcohol and Perillaldehyde

Perillyl alcohol is a naturally occurring monoterpene in citrus fruits, herbs, and spices with anticancer properties (Gould, 1995). Several animal-tumor models reported the anticancer action of perillyl alcohol in breast, liver, colon, and prostate cancer (Haag and Gould, 1994; Mills et al., 1995; Kelloff et al., 1996). Samouti et al. (1999) found perillyl alcohol induced transient expression of the c-jun and c-fos genes, as well as phosphorylation of c-jun protein-cultured breast-cancer cell. Both events are associated with activation of an activator protein (AP)-1-dependent reporter gene. These changes are associated with perillyl alcohol’s ability to induce apoptosis, or cell death. Phase I human clinical trials with perillyl alcohol indicated it is a relatively nontoxic compound for treating certain human tumors (Hudes et al., 2000; Ripple et al., 2000). Bardon and coworkers (2002) established the molecular mechanisms of perillyl alcohol and its major metabolite, perillic acid (PA), as antiproliferative agents using human colon-cancer cells. These monoterpenes arrested the growth of cancer cells by increasing the expression of the cdk inhibitor p21^Waf1/CiP1 and decreasing the expression of cyclin D1 and its partner, cdk4. The effect of perillyl alcohol on two human lung-cancer cell lines, H383, nonsmall cell lung cancer cells derived from adenocarcinoma and H322, bronchioloalveolar carcinoma cells, was reported recently by Xu and coworkers (2004). Perillyl alcohol stimulated or sensitized lungtumor cells to apoptosis via activation of caspase-3, a key executioner of apoptosis. This is evident in Figure P.74 where the highest dose of perillyl alcohol (1.5 mM) significantly decreased cell proliferation in H322 and H838 cells by 83% and 70%, respectively. The increased sensitivity of perillyl-alcohol-treated cells suggested it could be combined with other drugs to maximize chemotherapeutic effects. Ahn et al. (2003) showed the anticancer properties of perillyl alcohol on SCK mammary carcinoma cells of female A/J mice was significantly enhanced by hypothermia. The latter is used for treating certain human tumors, so that the synergism observed in this study could lead to a combination of perillyl alcohol and hyperthermia.

Perillyl alcohol. (Adapted from Zhang et al., J. Chromatrgr. B., 728:85–98, 1999.

In vitro studies with human carcinoma cell lines (BroTo and A5459) by Elgebede and coworkers (2003) found perillaldehyde only weakly induced apoptosis compared to perillyl alcohol, which probably involved a different mechanism.

FIGURE P.74 Perillyl alcohol inhibition of cell proliferation. H322 and H838 cells were treated with either 0.06% ethanol (vehicle controls) or perillyl alcohol at concentrations ranging from 0.25 to 1.5 mM for 1 and 5 days. Untreated cells served as an additional negative control. The sulforhodamine B (SRB) cell proliferation assay was performed. The individual bars represent the mean values±standard deviation of three individual experiments performed in triplicate. Asterisks (*) indicate values that are statistically signifcant at a minimal of p<0.05 relative to vehicle control (Xu, Toxicol. Applied Pharmacol., 195:232–246, 2004).

References

Ahn, K.-J., Lee, C.K., Choi, E.K., Griffin, R., Song, C.W., and Park, H.J., Cytoxicity of perillyl alcohol against cancer cells is potentiated by hyperthermia, Int. J. Radiat. Oncol. Biol. Phys., 57:813–819, 2003.

Bardon, S., Foussard, V., Fournel, S., and Loubat, A., Monoterpenes inhibit proliferation of human colon cancer cells by modulating cell cycle-related protein expression, Cancer Lett., 181:187– 194, 2002.

Elgebede, J.A., Flores, R., and Wang, R.C., Perillyl alcohol and perillaldehyde induced cell cycle arrest and cell death in Bro To and A549 cells cultured in vitro, Life Sci., 73:2831–2840, 2003.

Gould, M.N., Prevention and therapy of mammary cancer by monoterpenes, J. Cell. Biochem., 59 (Issue S22): 139–144, 1995.

Haag, J.D. and Gould, M.N., Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene, Cancer Chemother. Pharmacol., 34:477–483, 1994.

Hudes, G.R., Szarka, C.W., Adams, A., Ranganathan, S., McCauley, R.A., Weiner, L.M., Langer, C.J., Litwin, S., Yeslow, G., Halberr, T., Qian, M., and Gallo, J.M., Phase I Pharmacokinetic study of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies, Clin. Cancer. Res., 6:3071–3080, 2000.

Kelloff, G.J., Crowell, J.A., Hawk, E.T., Steele, V.E., Lubet, R.A., Boone, C.W., Covey, J.M., Doody, L.A., Omenn, G.S., Greenwald, P., Hong, W.K., Parkinson, D.R., Bagheri, D., Baxter, G.T., Blunden, M., Doeltz, M.K., Eisenhauer, K.M., Johnson, K., Longfellow, D.G., Knapp, G.G., Malone, W.F., Nayfield, S.G., Seifried, H.E., Swall, L.M., and Sigman, C.C., Strategy and planning for chemopreventive drug development. Clinical development plans: 1-Perillyl alcohol, J. Cell. Biochem., 268:137–148, 1996.

Mills, J.J., Chari, R.S., Boyer, I.J., Gould, M..N. and Jirtle, R.L., Induction of aoptosis in liver tumors by the monoterpene perillyl alcohol, Cancer Res., 55: 979–983, 1995.

Ripple, G.H., Gould, M.N., Arzoomanian, R.Z., Alberti, D., Feierabend, C., Simon, K., Binger, K., Tutsch, K.D., Pomplun, M., Wahamaki, A., Marnocha, R., Wilding, G., and Bailey, H.H., Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day, Clin. Cancer Res., 6:390–396, 2000.

Satomi, Y., Miyamoto, S., and Gould, M.N., Induction of AP-1 activity by perillyl alcohol in breast cancer cells, Carcinogenesis, 20:1957–1961, 1999.

Xu, M., Floyd, H.S., Greth, S.M., Chang, W.-C.L., Lohman, K., Stoyanova, R., Kucera, G.L., Kute, T.E., Willingham. M.C., and Miller, M.S., Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: Potential mechanisms for its chemotherapeutic effects, Toxicol. Appl. Pharmacol., 195:232–246, 2004.

Persimmon

Persimmon (Diospyros khaki) is grown in Asia, where the leaves are brewed into a tea for its health benefits, such as homeostasis, diuretic, constipation, and hypotension. These properties reflect the health-promoting effects of flavonoids, such as kaempferol, and the higher total, soluble, and insoluble dietary fibers, total phenols, epicatechin, gallic, and p-coumaric acids, as well as minerals Na, K, Mg, Ca, Fe, and Mn compared to apples (Gorinstein et al., 2001).

In vitro and in vivo studies with persimmon and grape extracts by Ahn et al. (2002) showed both were potent antioxidants. Using DPPH, both extracts exhibited similar free-radical- scavenging activities of around 87–88 percent, which was attributed to their high tannin contents. In vivo studies with Sprague-Dawley rats resulted in a significant inhibition of lipid peroxidation. However, Figure P.75 shows that the persimmon extract was more effective in lowering hepatic TBARS, secondary oxidation products, than the grape-seed extract. In addition, there was a corresponding reduction in hepatic lipid-peroxide levels accompanied by an increase in catalase and superoxide dismutase (SOD) levels.

References

Ahn, H.S., Jeon, T.I., Lee, J.Y., Hwang, S.G., Lim, Y., and Park, D.K., Antioxidative activity of persimmon and grape seed extract: In vitro and in vivo, Nutr. Res., 22:1265–1273, 2002.

Gorinstein, S., Zachwieja, Z., Folta, M., Barton, H., Piotrowicz, J., Zenser, M., Weisz, M., Trahktenbergh, S., and Belloso, O., Comparative content of dietary fibre, total phenolics, and minerals in persimmons and apples, J. Agic. Food Chem., 49:952–957, 2001.

FIGURE P.75 Effects of PSE compared to GSE on the amount of thiobarbituric-acid reactive substances (TBARS; top panel) and phosphatidylcholine hydroperoxide (PCOOH; bottom panel) in the liver of rats. Each bar represents the means±SEM of five rats. Mean values with different superscripts are significantly different (P<0.05). CON, control; PSE, persimmon seed extract; GSE, grape-seed extract. (From Ahn et al., Nutr. Res., 22:1265–1273, 2002. With permission.)

Phenols

see also Flavonoids Phenols and polyphenols are ubiquitous in plant foods and, depending on their bioavailability, may play an important role as antioxidants. A number of comprehensive reviews on the health aspects of polyphenols are recommended to the reader (Mahmoud et al., 2000; Zheng and Ramirez, 2000; Parr and Bolwell, 2000; Hollman, 2001). A large variety of plant phenols are synthesized via phenylpropanoid pathways, as shown in Scheme P.43. One of these, the flavonoids, consists of six different classes that account for more than 4,000 different compounds (see Flavonoids). The overall beneficial activities of phenols and polyphenols include their potent antioxidant activity, preventing oxidative damage to DNA, lipids, and proteins associated with prevention of chronic diseases. The inverse association between flavonol intake and cardiovascular disease points to their preventive role in atherosclerosis. The bioavailability of flavonoids in humans is only around 1 percent, and recent work by Lotito and Frei (2004) suggested that the increased plasma antioxidant capacity recorded in humans following apple consumption may not be due to apple-derived flavonoids but to the effect of fructose on urate.

References

Hollman, P.C.H., Evidence for health benefits of plant phenols: Local or systemic effects? J. Sci. Food Agric., 81:842–852, 2001.

Lotito, S.B. and Frei, B., The increase in human plasma antioxidant capacity after apple consumption is due to the metabolic effect of fructose on urate, not apple-derived antioxidant flavonoids, Free Rad. Biol. Med., 37:251–258, 2004.

Mahmoud, N.N., Carothers, A.M., Grunberger, D., Bilinski, R.T., Churchill, M.R., Martucci, C., Newmark, H.L., and Bertagnolli, M.M., Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis, Carcinogenesis, 21: 921–927, 2000.

Parr, A.J. and Bolwell, G.P., Phenols in the plant and in man, the potential for possible nutritional enhance ment of the diet by modifying the phenols content or profile, J. Sci. Food Agric., 80:985–1012, 2000.

Zheng, J. and Ramirez, V.D., Inhibition of mitochondrial proton F0F1-ATPase/ATPsynthase by polyphenolic phytochemicals, Br. J. Pharmacol., 130:1115–1123, 2000.

SCHEME P.43 Most plant phenols are synthesized via the phenylpropanoid pathway and share a common building block, the C6-C3 unit. (From Hollman, J. Sci. Food Agric., 81:842–852, 2001. With permission.)

2-Phenylethyl isothiocyanate (PEITC)

2-Phenylethyl isothiocyanate (PEITC) is formed in some Brassica species, such as watercress, by the action of myrosinase on its precursor gluconasturtiin (2-phenylethyl glucosinolate) (Scheme P.44). This occurs by chewing or in food preparation. PEITC is recognized as one of the most effective anticancer agents (Huang et al., 1998) by inhibiting phase I enzymes and activating phase II enzymes (Hecht et al., 1999). In addition, in vitro and in vivo studies showed PEITC had therapeutic value by inducing apoptosis in cells resistant to chemotherapy due to mutation of p53 (Huang et al., 1998; Xiao and Singh, 2002; Yang et al., 2002). Hu and coworkers (2003) reported induction of apoptosis in human HT-29 colon adenocarcinoma cells by PEITC was both time-dependent and dose-dependent, mediated via the mitochondrial caspase cascade, with activation of the mitogen-activated kinase JNK critical for initiation of the process. Using isolated hepatocyte mitochondria from rat hepatoma HepG2 cells, Rose et al. (2005) showed that decreased cell viability by PEITC was concentration dependent with an IC50 of 20 mM (Figure P.76). The inability of pharmacological inhibitors of mitochondrial permeability, cyclosporine A, trifluoperazine, and Bongkrekic acid, to prevent PEITC-induced apoptosis of HepG2 cells suggested the key target was the mitochondria. Apoptosis of HeG2 cells by PEITC appeared to be via the pore-forming ability of proapoptotic Bax.

SCHEME P.44 Generation of the phenylethyl isothiocyanate (PEITC) from gluconasturtiin (GNST) by myrosinase (MYR) action. (From Canistro et al., Mutat. Res., 545:23–35, 2004. With permission.)

FIGURE P.76 Concentrationdependant effects of PEITC on HepG2 cells as determined at 24 h using the crystal violet viability assay. Data are representative of three separate experiments (means±SD). (From Rose et al., Int. J. Biochem. Cell Biol., 37:100–119, 2005. With permission.)

References

Canistro, D., Della Croce, C., Iori, R., Barilla, J., Bronzetti, G., Poi, G., Cini, M., Caltavuturo, L., Perocco, P., and Paolini, M., Genetic and metabolic effects of gluconasturtiin, a glucosinolate derived from cruciferae, Mutat. Res., 545:23–35, 2004.

Hecht, S.S., Carmella, S.G., and Murphy, S.E., Effects of watercress consumption in urinary metabolites of nicotine in smokers, Cancer Epidemiol. Biomark. Prevent., 8:907–913, 1999.

Hu, R., Kim, B.R., Chen, C., Hebbar, V., and Kong, A.-N.T., The roles of JNK and apoptotic signaling pathways in PEITC-mediated responses in human HT-29 colon adenocarcinoma cells, Carcinogenesis, 24:1361–1367, 2003.

Huang, C., Ma, W.Y., Li, J., Hecht, S.S., and Dong, Z., Essential role of p53 in phenylethyl isothiocyanateinduced apoptosis, Cancer Res., 58:4102–4108, 1998.

Rose, P., Armstrong, J.S., Chua, Y.L., Ong, C.N., and Whiteman, M., β-Phenylethyl isothiocyanate mediated apoptosis: Contribution of Bax and the mitochondrial death pathway, Int. J. Biochem. Cell Biol., 37:100–119, 2005.

Xiao, D. and Singh, S.V., Phenethyl isothiocyanateinduced-apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases, Cancer Res., 62:3615–3619, 2002.

Yang, Y.M., Conaway, C.C., Chiao, J.W., Wang, C.X., Amin, S., Whysner, J., Dai, W., Reinhardt, J., and Chung, F.L., Inhibition of benzo(a)pyreneinduced lung tumorigenesis in A/J mice by dietary N-acetylcysteine conjugates of benzyl and phenylethyl isothiocyanates during the potentiation phase is associated with activation of mitogen-activated protein kinases and p-53 activity and induction of apoptosis, Cancer Res., 62:2–7, 2002.

Pheophytin and Pheophorbide

see also Chlorophyll and Chlorophyllin The methanol extracts from eight Japanese edible seaweeds were found to suppress genotoxininduced umu C gene expression in Salmonella typhimurium. The edible seaweeds with strong antigenotoxic properties were Porphyra tenera and Enteromorpha prolifera (Okai et al., 1994). The bioactives identified in P. tenera extracts were β-carotene, lutein, and chlorophyll a (Okai et al., 1996). Further work by Okai and Higashi-Okai (1997a) showed pheophytin a, a degradation product of chlorophyll a, was responsible for these suppressor effects. Pheophytin a and b were also identified as potent as antigenotoxic compounds in the nonpolyphenolic fraction of green tea, capable of suppressing the umu C gene (Okai and Higashi-Okai, 1997b). Subsequent work by Higashi-Okai et al. (1998) reported the antitumor suppressors in the nonphenolic fraction from green tea. Using a Salmonella typhimurium strain TA100, Chernomorsky and coworkers (1999) found the antimutagenic properties of chlorophyll derivatives, pheophytin, pyropheophytin, and pheophorbide, against the indirect-acting mutagen 3-methyl-cholanthrene, showed a similar doseresponse pattern (Figure P.77). However, in the presence of the direct-acting mutagen, N′-nitro-N′-nitrosoguanidine, derivatives acted quite differently, with the phytol-containing derivatives (pheophytin and pyropheophytin) being far more effective than pheophorbide, which lacked the phytol group. Thus, food sources containing these chlorophyll derivatives may have a role in cancer prevention.

Structure of chlorophyll derivatives. (From Chernomorsky et al., Teratogenesis Carcinogen. Mutagen., 19:313–322, 1999. With permission.)

Pheophytin a; R₁=CH₃, R₂=C20H₃₉
Pyropheophytin a; R₁=H; R₂=C₂₀H₃₉
Pheophorbide a; R₁=CH₃; R₂=H

Using yeast cells (Saccaromyces cerevisiae), Okai and Higashi-Okai (2001) reported that chlorophyll a and pheophytin a from green tea were both more effective than chlorophyllin in preventing the endocrine disrupter, p-nonylphenol, from suppressing cell growth and cellular respiration. The antioxidant properties of chlorophyll a and pheophytin a reported previously by Endo et al. (1985) and Higashi-Okai et al. (2000), could explain, in part, the mechanism involved, as well as their ability to adsorb or bind p-nonylphenol.

References

Chernomorsky, S., Poretz, R., and Segelman, A., Effect of dietary chlorophyll derivatives on mutagenesis and tumor cell growth, Teratogenesis Carcinogen. Mutagen., 7:313–322, 1999.

Endo, Y., Usuki, R., and Kaneda, T., Antioxidant effects of chlorophyll and pheophytin on the autoxidation of oils in the dark, I, Comparison of the inhibitory effects, J. Am. Oil Chem. Soc., 62:1375–1387, 1985.

Higashi-Okai, K., Otani, S., and Okai, Y., Potent suppressor of pheophytin a and b from the nonpolyphenolic fraction of green tea (Camellia sinensis) against tumor promotion in mouse skin, Cancer Lett., 129:223–228, 1998.

Higashi-Okai, K., Taniguchi, M., and Okai, Y., Potent antioxidative activity of non-polyphenolic fraction of green tea (Camellia sinensis)-association with pheophytins a and b, J. Sci. Food Agric., 80:117–120, 2000.

Okai, Y. and Higashi-Okai, K., Pheophytin a is a potent suppressor against genotoxin-induced umu C gene expression in Salmonella typhimurium (TA 1535/pSK 1002), J. Sci. Food Agric., 74:531–535, 1997a.

Okai, Y. and Higashi-Okai, K., Potent suppressing activity of the non-polyphenolic fraction of green tea (Camellia sinensis) against genotoxin-induced umu C gene expression in Salmonella typhymurium (TA 1535/pSK 1002)-association with pheophytins a and b, Cancer Lett., 120:117–123, 1997b.

Okai, Y. and Higashi-Okai, K., Protective effects ofchlorophyll a and pheophytin a derived from green tea (Camellia sinensis) on p-nonylphenol-induced cell growth inhibition and oxygen radical generation in yeast (Saccharomyces cerevisiae), J. Sci. Food Agric., 81:1443–1446, 2001.

Okai, Y., Higashi-Okai, K., Nakamura, S., Yano, T., and Otani, S., Suppressive effects of the extracts of Japanese edible seaweeds on mutagen-induced umu C gene expression in Salmonella typhimurium (TA 1535/pSK 1002) and tumor promoter-dependent ornithin decarboxylase induction in BALB/c3T3 fibroblast cells, Cancer Lett., 87:25–32, 1994.

Okai, Y., Higashi-Okai, K., Yano, Y., and Otani, S., Identification of antimutagenic substances in an extract of edible red alga, Porphyra tenera (Asausanori), Cancer Lett., 100:235–240, 1996.

FIGURE P.77 Antimutagenic activity of pheophytin a (●), pyropheophytin a (▲), and pheophorbide a (○) against 3-methylcholanthrene. (From Chernomorsky et al., Teratogenesis Carcinogen. Mutagen., 19:313–322, 1999. With permission.)

Phloretin

see also Phloridzin Phloretin, a polyphenolic compound found in the root bark of apple trees, is the aglycone of phloridzin. It was recently found to enhance skin permeation of a number of drugs (Valenta et al., 2001; Valenta and Nowak, 2001; Auner et al., 2003a, b). Research by Curtis-Prior et al. (1980) showed that phloretin derivatives were antagonsists of prostaglandins, which pointed to their therapeutic potential as anti-inflammatory agents. Auner and Valenta (2004) confirmed the ability of phloretin to increase lidocaine skin permeation. The effect of lidocaine, a local anesthetic used to suppress burning, itching, surgical operations, injections, and dermatological diseases, was enhanced 1.39-fold in a hydrophilic formulation and 1.25 and 1.76 in lipophilic formulations.

Phloretin. (From Valenta et al., Eur. J. Pharmaceut. Biopharmaceut., 57:329–336, 2004. With permission.)

Valenta and coworkers (2004) studied the mechanism of phloretin and 6-ketocholestanol interaction with the lipid layer which decreased the lipid phase transition temperature of 1,2dimyristyl-sn-3-phosphocholine (DMPC) and 1,2-palmitoyl-snglycero-3-phosphocholine (DPPC) liposomes, resulting in a higher fluidity of the membrane. Phloretin modified the binding and translocation rates of hydrophobic ions in lipid-vesicle systems, resulting in lowering and raising of the internal dipole potential (Franklin and Cafiso, 1993).

References

Auner, B.G. and Valenta, C., Influence of phloretin on the skin permeation of lidocaine from semisolid preparations, Eur. J. Pharm. Biopharm., 57:307–312, 2004.

Auner, B.G., Valenta, C., and Hadgraft, J., Influence of lipophilic counter-ions in combination with phloretin and 6-ketocholestanol on the skin permeation of 5-aminolevulinic acid, Int. J. Pharm., 255:109–113, 2003a.

Auner, B.G., Valenta, C., and Hadgraft, J., Influence of phloretin and 6-ketocholestanol on the skin permeation of sodium-fluorescein, J. Control Rel., 89: 321–328, 2003b.

Curtis-Prior, P.P., Oblin, A.P., Bennet, A., Parkinson, N.A., and Orloff, A.M., Polyphloretin phosphate (PPP) antagonists of prostaglandin action also inhibits prostaglandin biosynthesis in vitro, J. Pharm. Pharmacol., 42:660–662, 1990.

Franklin, J.C. and Cafisco, D.S., Internal electrostatic potentials in bilayers: Measuring and controlling dipole potentials in lipid vesicles, Biophys. J., 65: 289–299, 1993.

Valenta, C., Cladera, J., O’Shea, P., and Hadgraft, J., Effect of phloretin on the percutaneous absorption of lignocaine across human skin, J. Pharm. Sci., 90: 485–492, 2001.

Valenta, C., Nowak, M., and Hadgraft, J., Influence of phloretin and 6-ketocholestanol on the permeation of progesterone through porcine skin, Int. J. Pharm., 217:79–86, 2001.

Valenta, C., Steininger, A., and Auner, B.G., Phloretin and 6-ketocholestanol: Membrane interactions studied by a phospholipid/polydiacetylene colorimetric assay and differential scanning calorimetry, Eur. J. Pharmaceut. Biopharmaceut., 57:329–336, 2004.

Phloridzin

see also Apples and Phloretin Phloridzin, a poly phenol found in apples, has been used to inhibit the intestinal Na+/glucose transporter (SGLT1) (Hirayama et al., 1998). Mizuma and Awazu (1998) reported phloridzin was metabolized to its aglycone, phloretin, with both inhibiting glucuronidation of p-nitrophenol, acetaminophen, and 1-naphthol in rats. Inhibition of glucuronidation metabolism improves the intestinal absorption of those drugs susceptible to glucuronidation. A recent study by Andlauer and coworkers (2004) found phloridzin amplified the absorption of the isoflavone, genistin, 2.5-fold. Isoflavones are generally poorly absorbed so that a high intake is normally required to ensure their chemoprevention effects. A combination of nutraceuticals, such as genistin, with functional phloridzin-containing foods provides a novel way of enhancing genistin absorption and increasing its efficacy in cancer prevention.

Phloridzin. (From Valenta et al., Eur. J. Pharmaceut. Biopharmaceut., 57:329–336, 2004.)

The antioxidant and radical-scavenging activities of polyphenols, including phloridzin and 3-hydroxy-phloridzin, was reported in apple pomace, the waste product produced in the processing of apple juice. The health-protecting properties of apples may be attributed to these compounds, as Hertog and coworkers (1993) provided data that suggested that men who ate 110 g of apple or day had a 49 percent lower risk factor for heart attack compared to those eating much less (18 g).

References

Andlauer, W., Kolb, J., and Furst, P., Phloridzin improves absorption of genistin in isolated rat small intestine, Clin. Nutr., 23:989–995, 2004.

Hertog, M.G.L., Feskens, E.J.M., Kromhout, D., Hollman, P.C.H., Hertog, M.G.L., and Katan, M.B., Dietary antioxidant flavonids and risk of coronary heart disease: The Zutphen elderly study, Lancet, 342:1007–1012, 1993.

Hirayama, B.A., Lostao, M.P., Panayotova-Heiermann, M., Loo, D.D.F., Turk, E., and Wright, E.M., Kinetic and specificity differences between rat, human, and rabbit Na1-glucose co-transporters (SGLT-1), Am. J. Physiol., 270:G919–926, 1998.

Mizuma, T. and Awazu, S., Inhibitory effect of phloridzin and phloretin on glucuronidation of p-nitrophenol, acetaminophen and 1-napthol: Kinetic administration of the influence of glucuronidation metabolism on intestinal absorption in rats, Biochem. Biophys. Acta, 1425:398– 404, 1998.

Valenta, C., Steininger, A., and Auner, B.G., Phloretin and 6-ketocholestanol: Membrane interactions studied by a phospholipid/polydiacetylene colorimetric assay and differential scanning calorimetry, Eur. J. Pharmaceut. Biopharmaceut., 57:329–336, 2004.

Phosphatides

see also Phosphatidylcholine and Phosphatidylserine These include numerous lipids in which phosphoric acid, as well as fatty acids, are esterified to glycerol and are found in all living cells and in bilayers of plasma membranes. Phospholipids have been associated with a number of health benefits. A glycerol-free phospholipid analogue, hexadecyl-phosphocholine (HePC), was shown by Wieder et al. (1996) to exhibit antitumor properties using cultured human breast fibroblasts. The antitumor activity appeared to be related to activation of cellular phospholipase D.

References

Wieder, T., Zu-Chuan, Z., Geilen, C.C., Orfanosa, C.E., Giulianob, A.E., and Cabot, M.C., The antitumor phospholipid analog, hexadecylphosphocholine, activates cellular phospholipase D, Cancer Lett., 100:71–79, 1996.

Phosphatidylcholine

Phosphatidylcholine (PC), or lecithin, constitutes a major portion of cellular phospholipids and displays unique molecular species in different cell types and tissues. PC is also the major delivery form of the essential nutrient choline and is involved in the hepatic form, which is involved in the hepatic export of very-low-density lipoproteins. The main roles of PC are the flow of information within cells from DNA to RNA to proteins and the formation of cellular energy and intracellular communication or signal transduction. PC also has a marked fluidizing effect on cellular membranes. Decreased cell-membrane fluidization and breakdown of cell-membrane integrity, as well as impairment of cell-membrane repair mechanisms, are associated with a number of disorders, including liver disease, neurological diseases, various cancers, and cell death.

Many agents that perturb PC homeostasis also induce cell death, but the signaling pathways that mediate this cell death have not been well defined (Cui and Houweling, 2002). PC is absorbed into the mucosal cells of the small intestine, mainly in the duodenum and upper jejenum, following some digestion by the pancreatic enzyme phospholipase, producing lysophosphatidylcholine, which is transported by the lymphatics in the form of chylomicrons to the blood. PC is transported in the blood in various lipoprotein particles, including very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL), and is then distributed to various tissues in the body. Some PC is incorporated into cell membranes and some is metabolized to choline, fatty acids, and glycerol.

PC may have a beneficial effect by restoring liver function in a number of disorders (Hatashi et al., 1999), including alcoholic fibrosis and possibly viral hepatitis (Canty and Zeisel, 1994). Dietary lecithin (a complex mixture of phospholipids and other lipids) has been used in emergencies and in the treatment of atheroma plaques in cardiac diseases. It promotes a return to normal of the plasma lipoprotein-distribution profile and the removal of lipid from established atherosclerotic plaques in Dutch-Belted rabbits (Hunt and Duncan, 1985). Recently, PC was used to treat localized fat deposits, such as lower eyelid fat pads (Hexsel et al., 2003; Ablon and Rotunda, 2004).

Some studies found PC had a positive effect on memory (Ladd et al., 1993; Chung et al., 1995). Masuda and coworkers (1998) found egg PC, together with vitamin B₁₂, improved memory impairment of rats with nucleus basalis Magnocellularis (NBM) lesions. PC has also been used to treat manic conditions (Cohen et al., 1982) and in some tardive dyskinesia (Gelenberg et al., 1989). PC has even been evaluated in Parkinson’s disease (Tweedy and Garcia, 1982). Cytidine 5′-diphosphocholine, an essential intermediate in the biosynthetic pathway of PC, was reported to be effective as cotherapy for Parkinson’s disease (Secades and Frontera, 1995) and was recently shown to have a positive effect on memory, with demonstrated hippocampal morphology resembling that of younger animals (Crespo et al., 2004). There is some inconclusive evidence that PC may be useful in managing Alzheimer’s disease and some cognitive disorders (Higgins and Flicker, 2003; McDaniel et al., 2003).

A possible future role for PC suggested by Gallo et al. (2003) is in cancer therapy. A complex of silybin/phosphatidylcholine (IdB 1016) appeared to have clinical potential in the management of recurrent ovarian cancer.

References

Ablon, G., and Rotunda, A.M., Treatment of lower eyelid fat pads using phosphatidylcholine: Clinical trials and review, Dermatol. Surg., 30:422–421, 2004.

Canty, D.J. and Zeisl, S.H., Lecithin and choline in human health and disease, Nutr. Rev., 52:327– 339, 1994.

Chung, S.Y., Moriyama, T., Uezu, E., Uezu, K., Hirata, R., Yohena, N., Masuda, Y., Kokubu, T., and Yamamoto, S., Administration of phosphatidylcholine increases brain acetylcholine concentration and improves memory in mice with dementia, J. Nutr., 125:1484–1489, 1995.

Cohen, B.M., Lipinski, J.F., and Altesman, R.I., Lecithin in the treatment of mania: Double-blind, placebo-controlled trials, Am. J. Psychiatry, 139:1162–1164, 1982.

Crespo, D., Megias, M., Fernandez-Viadero, C., and Verguda, R., Chronic treatment with a precursor of cellular phosphatidylcholine ameliorates morphological and behavioral effects of aging in the rat hippocampus, Am. N.Y. Acad. Sci., 1019:41–43, 2004.

Cui, Z. and Houweling, M., Phosphatidylcholine and cell death, Biochem. Biophys. Acta, 1585:87– 96, 2002.

Gallo, D., Giacomelli, S., Ferlini, C., Raspaglio, G., Apollonio, P., Prislei, S., Riva, A., Morazzoni, P., Bombardelli, E., and Scambia, G., Antitumor activity of the silybin-phosphatidylcholine complex, IdB 1016, against human ovarian cancer, Eur. J. Cancer, 39:2403–2410, 2003.

Gelenberg, A.J., Wojcik, J., Falk, W.E., Bellinghausen, B., and Joseph, A.B., CDP-choline for the treatment of tardive dyskenisia: A small negative series, Compr. Psych., 30:1–4, 1989.

Hayashi, H., Tanaka, Y., Hibino, H., Umeda, Y., Kawamitsu, H., Fujimoto, H., and Amakawa, T., Beneficial effect of salmon roe phosphatidylcholine in chronic liver disease, Curr. Med. Res. Opin., 15: 177–184, 1999.

Hexsel, D., Serra, M., Mazzuco, R., Dal’Forno, T., and Zechmeister, D., Phosphatidylcholine in the treatment of localized fat, J. Drugs Dermatol., 2: 511–518, 2003.

Higgins, J.P. and Flicker, L., Lecithin for dementia and cognitive impairment, The Cochrane Database Syst. Rev., 3:CD001015, 2003.

Hunt, C.E. and Duncan, L.A., Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin, Br., J. Exp. Pathol., 66:35–46, 1985. Ladd, S.L., Sommer, S.A., LaBerge, S., and Toscano, W., Effect of phosphatidylcholine on explicit memory, Clin. Neuropharmacol., 16:540–549, 1993.

Masuda, Y., Kokubu, T., Yamashita, M., Ikeda, H., and Inoue, S., EFF phosphatidylcholine combined with vitamin B12 improved memory impairment following lesioning of nucleus basalis in rats, Life Sci., 62:813–822, 1998.

McDaniel, M.A., Maier, S.F., and Einstein, G.O., Brain-specific nutrients: A memory cure? Nutrition, 19:957–975, 2003.

Secades, J.J. and Frontera, G., CDP-choline: Pharmacological and clinical review, Methods Find Exp. Clin. Pharmacol., 17(Suppl. B):1–54, 1995.

Tweedy, J.R. and Garcia, C.A., Lecithin treatment of cognitively impaired Parkinson’s patients, Eur. J. Clin. Invest., 12:87–90, 1982.

Phosphatidylserine

Phosphatidylserine (PS), a natural component of the brain cortex, is the major phospholipid in the outer surface of brain-sy naptic membranes. It plays an important role in signal transduction, secretory-vesicle release, and cell-to-cell communication (Nishizuka, 1984; Blokland et al., 1999). PS may be the signal by which apoptotic cells are recognized and phagocytosed (Brauer, 2003). Studies with geriatric patients suffering from Alzheimer’s or Parkinson’s disease or arteriosclerotic encephalopathy suggested that prolonged treatment with PS particularly improved attention, memory, withdrawal and apathy, sleep disturbances, and mood (Maggioni et al., 1990). A significant improvement in depressive symptomatology in patients with major depressive disorders was found in subsequent studies, also with PS administration compared to controls (Brambilla et al., 1996; Brambilla and Maggioni, 1998). Crook et al. (1991) treated patients with age-associated memory impairment with a daily dose of PS (100 mg/day tid) over 12 weeks and found improved performance tests related to learning and memory tasks of daily life compared to those receiving the placebo. Castilho et al. (2004) found PS exerted an antidepressive effect in rats using the forced swimming test but did not act as a cognitive enhancer, as it was ineffective in the watermaze test.

References

Blokland, A., Honig, W., Brouns, F., and Jolles, J., Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle-aged rats: Comparison of bovine cortex PS with egg PS and soybean PS, Nutrition, 15:778–783, 1999.

Brambilla, F. and Maggioni, M., Blood levels of cytokines in elderly patients with major depressive disorders, Acta Psychiatr. Scand., 97:309–313, 1998.

Brambilla, F., Maggioni, M., Panerai, A.E., Sacerdote, P., and Cenacchi, T., Beta-endorphin concentration in peripheral blood mononuclear cells of elderly depressed patients—effects of phosphatidylserine therapy, Neuropsychobiology, 34:18–21, 1996.

Brauer, M., In vivo monitoring of apoptosis, Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 27:323–33, 2003.

Castilho, J.C., Perry, J.C., Andreatini, R., and Vital, M.A.B.F., Phosphatidylserine: An antidepressive or a cognitive enhancer? Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 28:731–738, 2004.

Crook, T.H., Tinklelberg, J., Yesavage, J., Petrie, W., Nunzi, M.G., and Massari, D.C., Effects of phosphatidylserine in aged-associated memory impairment, Neurology, 41:644–649, 1991.

Maggioni, M., Picotti, G.B., Bondiolotti, G.P., Panerai, A., Cenacchi, T., Nobile, P., and Brambilla, F., Effects of phosphatidylserine therapy in geriatric patients with depressive disorders, Acta Psychiatr. Scand., 81:265–270, 1990.

Nishizuka, Y., Turnover of inositiol phospholipids and signal transduction, Science, 225:1365– 1370, 1984.

Phospholipids

see Phosphatides, Phosphatidylcholine, and Phosphatidylserine

Phosvitin Phosvitin, a phosphoprotein known as an iron-carrier in egg yolk, binds almost all of the yolk iron. The formation of phosvitin-Fe complex promotes the precipitation of Fe in the small-intestinal tract, which may be responsible for the poor iron availability of egg and egg yolk (Sato et al., 1984). Ishakawa et al. (2004) reported that phosvitin acts as a natural antioxidant by chelating iron ions. It accelerates Fe(II) autoxidation and thus decreases the availability of Fe(III) for participation in the OH-generating Fenton reaction. These results provide insight into the mechanism of protection of the developing embryo against iron-dependent oxidative damage. Phosvitin was found to be more effective in cooked ground pork compared with uncooked, salted ground pork (Lee et al., 2002). Kobayashi et al. (2004) demonstrated that the role of phosvitin in bone formation was to enhance nucleation of hydroxyapatite crystals on collagen in the same way as that observed in human bone.

References

Ishikawa, S., Yano, Y., Arihara, K., and Itoh, M., Egg yolk phosvitin inhibits hydroxyl radical formation from the Fenton reaction, Biosci. Biotechnol. Biochem., 68:1324–1331, 2004.

Kobayashi, N., Onuma, K., Oyane, A., and Yamazaki, A., The role of phosvitin for nucleation of calcium phosphates on collagen, Key Eng. Materials, 254–256:537–540, 2004.

Lee, S.K., Han, J.H., and Decker, E.A., Antioxidant activity of phosvitin in phosphatidylcholine liposomes and meat model, J. Food Sci., 67:37–41, 2002.

Sato, R., Lee, Y.S., Noguchi, T., and Naito, H., Iron solubility in the small intestine of rats fed egg yolk protein, Nutr. Rep. Intern., 30:1319–1326, 1984.

Phyllanthus

Plants of the genus Phyllanthus (family Euphorbiaceae) are found in most tropical and subtropical countries. They have been used in folk medicine to treat kidney and urinarybladder disturbances, intestinal infections, diabetes, and hepatitis B. Studies conducted on extracts and purified compounds from these plants by Calixto and coworkers (1998) confirmed their efficacy as an antiviral, as well as in the treatment of genitourinary disorders, and as antinociceptive agents. They also found that Phyllanthus had potential therapeutic benefits in the management of hepatitis B. nefrolitase and in painful disorders. The leaves of Phyllanthus were shown earlier by Ihantola-Vormisto et al. (1997) to exert inhibitory activity on human polymorphonuclear leukocytes and antipyretic and platelets, which confirmed their antiinflammatory and antipyretic properties for use in traditional medicine. The anti-inflammatory properties of standardized Phyllanthus extracts were demonstrated by Kiemer and coworkers (2003) by their ability to inhibit induction of endoxin-unduced nitric-oxide synthase (iNOS), cyclooxygenase (COX-2), and TNF-α production in rat Kuppfer cells, in RAW264.7 macrophages, and in human whole blood. The significant inhibition of TNF-α in Male BalbA2 mice in the presence of the Phyllanthis extract is shown in Figure P.78.

FIGURE P.78 In vivo inhibition of TNF-α production by P. amarus extract (P.a.). Male BalbA2 mice received either 45 mg/kg Phyllanthus extract or saline/DMSO i.p. 30 min later, mice were injected with 500 mg/kg galactosamine i.p., and immediately afterwards with 1.5 mg/kg of LPS(L/G). After 90 min, a serum sample was obtained by tail bleeding and murine TNF-α was determined by ELISA. Three independent experiments were carried out with four animals each. TNF-α level of the respective control group was normalized to 100 percent. Data are expressed as means±SEM. **p<0.01 represents statistical differences from animals treated with LPS/galactosamine only. (From Kiemer et al., J. Hepatol., 38:289–297, 2003. With permission.)

Huang et al. (2004) recently demonstrated the anticancer properties of Phyllanthus urinaria on human myeloid leukemia (HL-60) cells, which appeared to be mediated via a ceramide-related pathway. An increase in the inhibition of HIV-1 reverse transcriptase was reported by Wagner and Notka (2002) to be linear, with increasing concentrations of gallotannins extracted from Phyllanthus, suggesting its potential for preventing and treating retrovi-rus-related diseases, such as human immunodeficiency virus (HIV).

References

Calixto, J.B., Santo, A.R.S., Filho, C.V., and Yunes, R.F., A review of the plants from the genus Phyllanthus: Their chemistry, pharmacology, and therapeutic potential, Med. Res. Rev., 18:225– 258, 1998.

Huang, S-T., Yang, R.-C., Chen, M.-Y., and Pang, J.-H.S., Phyllanthus urinaria induces the Fas receptor/ ligand expression and ceramide-mediated apoptosis in HL-60 cells, Life Sci., 75:339– 351, 2004.

Ihantola-Vormusto, A., Summanen, J., Kankaanranta, H., Vuorela, H., Asmawi, Z.M., and Moilanen, E., Anti-inflammatory activity of extracts from leaves of Phyllanthus emblica, Planta Med., 63:518–524, 1997.

Kiemer, A.K., Hartung, T., Huber, C., and Vollmar, A.M., Phyllanthis amarus has antiinflammatory potential by inhibition of iNOS, COX-2, and cytokines via the NF-κB pathway, J. Hepatol., 38:289–297, 2003.

Wagner, R. and Notka, F., Phyllanthus-denved com pounds for the prevention and/or treatment of diseases associated with a retrovirus, PCT Int. Appl., 35 p., 2002.

Phytic acid

Phytic acid (myo-inositol hexaphosphate, IP₆) is the major storage form of phosphorus and accounts for 1–5 percent by weight of edible legumes, cereals, and oilseeds (Graf and Eaton, 1995). Historically, phytic acid was considered to be an antinutrient because of its ability to bind divalent cations, such as calcium, magnesium, zinc, and iron, reducing their bioavailability (Reddy et al., 1989). However, it has since been recognized as an antioxidant because of its potent inhibi tion of iron-catalyzed hydroxyl-radical formation (Rimbach and Pallauf, 1998). In addition, phytic acid has also been shown to have anticarcinogenic (Shamsuddin et al., 1996), as well as hypoglycemic and hypolipidemic, (Rickard and Thompson, 1997) properties.

Structure of phytic acid. (From Chen and Li, J. Chromatogr. A., 1018:41–52, 2003. With permission.)

Obata (2003) examined the effect of phytic acid on the neurotoxin 1-methyl-4- phenylpyridinium (MPP+), a potent Parkinson-causing reagent formed in the brain from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Phytic acid suppressed the ability of this neurotoxin to induce hydroxyl-radical generation by chelating the required iron, suggesting its clinical potential as an antioxidant.

Phytic acid was shown earlier by Midorikawa et al. (2001) to prevent the formation of reactive-oxygen species, such as 8-oxodG, in cultured cells treated with an H₂O₂-generating system. The dramatic reduction in the formation of oxidative DNA damage in the presence of phytic acid is evident from Figure P.79 compared to the inability of myoinositol to inhibit 8-oxodG formation. The antioxidant properties of phytic acid were due to its ability to chelate transition metal ions. The possible role of phytic acid in cancer prevention was further confirmed by Muraoka and Miura (2004), who showed that phytic acid, and not myo-inositol, inhibited xanthine oxidase, the enzymatic source of superoxide (O₂−). In addition, phytic acid also prevented the formation of ADP-iron-oxygen complexes. The potential of phytic acid to prevent the formation of oxygen radicals in the intestine could prevent the development of chronic diseases, such as cancer.

FIGURE P.79 Formation of 8-oxodG in calf thymus DNA induced by H₂O₂ and Cu(II) in the presence of phytic acid or myo-inositol. Calf thymus DNA fragments (100 μM/base) were incubated with 20 μM CuCl₂, 100 μM H₂O₂, and indicated concentrations of phytic acid (closed circles) or myoinositol (open circles) at 37°C for 15 min. After ethanol precipitation, the DNA was digested into nucleosides with nuclease P1 and calf-intestine phosphatase and analyzed with an HPLC-ECD system. Intersection of dotted lines showed the concentration of phytic acid to inhibit 8-oxodG formation. (From Midorikawa et al., Biochem. Biophys. Res. Commun., 288:552–557, 2001. With permission.)

A systematic review of phytic acid as a novel broad-spectrum, antineoplastic agent by Fox and Eberl (2002) suggested its role in cancer prevention warranted phase I and phase II human clinical trials.

References

Chen, Q.-C. and Li, B.W., Separation of phytic acid and other related inositol phosphates by highperformance ion chromatography and its applications, J. Chromatogr. A., 1018:41–52, 2003.

Fox, C.H. and Eberl, M., Phytic acid (IP6), a novel broad spectrum anti-neoplastic agent: A systematic review, Comp. Then Med., 10:229–234, 2002.

Graf, E. and Eaton, J.W., Antioxidant function of phytic acid, Free Rad. Biol. Med., 8:61–69, 1990.

Midorikawa, K., Murata, M., Oikawa, S., Hiraku, Y., and Kawanishi, S., Protective effect of phytic acid on oxidative DNA damage with reference to cancer chemoprevention, Biochem. Biophys. Res. Commun., 288:552–557, 2001.

Muraoka, S. and Miura, M., Inhibition of xanthine oxidase by phytic acid and its antioxidative action, Life Sci., 74:1691–1700, 2004.

Obata, T., Phytic acid suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum, Brain Res., 978:241–244, 2003.

Reddy, N.R., Pierson, M.D., Sathe, S.K., and Salunkhe, D.K., Phytates in Cereals and Legumes, CRC Press, Boca Raton, Florida, 1989, p. 152.

Rickard, S.E. and Thompson, L.U., Interactions and biological effects of phytic acid, in Antinutrients and Phytochemicals in Food, ACS symposium series No. 662, Shahidi, F., Ed., American Chemical Society, Washington, D.C., 1997, pp. 294–312.

Rimbach, G. and Pallauf, J., Phytic acid inhibits free radical formation in vitro but does not affect liver oxidant or antioxidant status in growing rats, J. Nutr., 128:1950–1955, 1998.

Shamsuddin, A.M., Yang, G.Y., and Vucenik, I., Novel anti-cancer functions of IP6: growth inhibition and differentiation of human mammary cancer cell lines in vitro, Carcinogenesis, 16:3287–3292, 1996.

Phytoestrogens

see also Genistein, Daidzein, and Matairesinol Phytoestrogens are a group of plant compounds that exert both estrogenic and antiestrogenic properties. The four separate plant families of phenolic compounds recognized as phytoestrogens are isoflavonoids, stilbenes, lignans, and coumestans (Scheme P.45). The richest plant sources are isoflavones in soybeans and lignans in flaxseed products (Tham et al., 1998). The anticancer properties of both isoflavonoids and lignans are thought to be responsible for the low incidence of prostate cancers by influencing both endocrine and growth-factor signaling pathways. Phytoestrogens from soybean, genistein and daidzein, were both found by Karamsetty and coworkers (2001) to restore the impaired-relaxation response to nitric-oxide release in pulmonary arteries isolated from chronically hypoxic rats. The latter condition is associated with pulmonary hypertension. For an excellent review of this subject, the article by Cornwell and coworkers (2004) is recommended.

References

Cornwell, T., Cohick, W., and Raskin, I., Dietary phytoesterogens and health, Phytochemistry, 65: 995–1016, 2004.

Karamsetty, M.R., Klinger, J.R., and Hill, N.S., Phytoestrogens restore nitric oxide-mediated relaxation in isolated pulmonary arteries from chronically hypoxic rats, Pharmacol. Exp. Ther., 297:968–974, 2001.

Tham, D.M., Gardner, C.D. and Haskell, W.L., Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechnistic evidence. J. Clin. Endocrinol. Metab., 83: 2223–2235, 1998.

SCHEME P.45 Structure of phytoestrogens, genistein, coumestrol, trans-resveratrol, and matairesinol. (From Cornwell et al., Phytochemistry, 65:995–1016, 2004. With permission.)

Phytohemagglutinins

see also Lectins

Phytohemagglutinins (PHA), or lectins, are proteins that bring about the agglutination of red blood cells. They are heat-labile and readily destroyed during normal food processing. Previous studies showed that a diet containing lectin a phytohemagglutinins from raw kidney bean markedly diminished the growth of Krebs II non-Hodgkin lymphoma (NHL) tumors in NMRI mice (Pryme et al., 1994, 1996, 1998). The reduced rate of growth was dose-dependent within the range of 0.45–3.5 mg/g of PHA in the diet (Pryme et al., 1996). Pryme and coworkers (1999) allowed the NMRI mice to develop non-Hodgkin lymphoma tumors for five days prior to feeding different levels of PHA to determine whether feeding the raw kidney lectin was also effective in reducing tumor growth. These researchers found that including PHA in the diet five days after injecting NHL tumors still reduced the progression of tumor development. This work suggested that further reduction in tumor proliferation might be achieved through manipulation of the diet with PHA and reduced protein.

References

Pryme, I.F., Bardocz, S., Grant, G., Pusztai, A., and Pfuller, A., The plant lectins PHA and ML-1 suppress the growth of a lymphosarcoma tumor in mice, in Effects of Antinutrients on the Nutritional Value of Legume Diets, Cost 98 vol. 5, Bardocz, S., Pfuller, U., and Pusztai, A., Eds., EC Publications, Luxemberg, 1998, pp. 86–90.

Pryme, I.F., Pusztai, A., and Bardocz, S., A diet containing the lectin phytohaemagglutinin (PHA) slows down the proliferation of Krebs II cell tumors in mice, Cancer Lett., 76:133–137, 1994.

Pryme, I.F., Bardocz, S., Pusztai, A., and Ewen, S.W.B., The growth of an established murine non-Hodgkin lymphoma tumor is limited by switching to a phytohaemagglutinin-containing diet, Cancer Lett., 146:87–91, 1999.

Pryme, I.F., Pusztai, A., and Bardocz, S., Phytohemagglutinin-induced gut hyperplasia and the growth of a mouse lymphosarcoma, J. Exp. Ther. Oncol., 1:171–176, 1996.

Phytosterols

Phytosterols are plant sterols differing very slightly in structure from cholesterol by the presence of an ethyl or methyl group at C-24 in the side chain (Scheme P.46). There are more than 100 different phytosterols, but the major ones are β-sitosterol, campesterol, and stigmasterol. Phytosterols stabilize the phospholipid bilayers in plant-cell membranes, as cholesterol does in animal-cell membranes. The fully saturated form of phytosterols (containing no double bond at the 5,6 position) are the phytostanols, which are present in only trace amounts but can also be formed by hydrogenation of phytosterols. On average, we consume approximately 250 mg per day of phytosterols from vegetable oils, cereals, fruits, and vegetables (Hicks and Moreau, 2001; Conner, 1968). In comparison, we consume around 25 mg per day of phytostanols (Conner, 1968; Cerqueira et al., 1979). The ability of phytosterols to lower cholesterol has been well documented (Pollak and Kritchevsky, 1981; Ling and Jones, 1995; Jones et al., 1997; Moghadasian and Frolich, 1999; Law, 2000). In fact, sitosterol was marketed as a drug for lowering cholesterol during the 1950s, but its poor solubility and bioavailability, plus the introduction of “statin” drugs, rapidly diminished its use. Scientists in Finland, however, improved the solubility of phytosterols by esterification which resulted in the first commercial production of phytosterol-containing margarines (Miettinen et al., 1996). Research subsequently showed that 2–3 g/day of phytostanyl ester-containing margarine consistently reduced LDL-cholesterol levels.

Clinical studies on the cholesterol-lowering properties of esterified phytosterols have shown they consistently lower serum LDL cholesterol. Miettingen et al. (1995) showed that consumption of around 23 g/day of a fat spread enriched with 10 percent hydrogenated sterols lowered LDL-cholesterol levels by 10–14 percent. A randomized, double-blind, placebo-controlled crossover study by Neil et al. (2003) showed patients with heterozygous familial hypercholesterolemia fed a vegetable-oil enriched fat spread reduced LDL cholesterol by 10–15 percent. Mussner and coworkers (2002) found that patients with mild to moderate hypercholesterolemia all had reduced LDL-cholesterol levels when fed a 1.83-g/day dosage of phytosterol esters. The most marked reduction in LDL-cholesterol levels, however, were observed in subjects with a high intake of cholesterol, energy, total fat, and saturated fat and with a high baseline absorption of cholesterol. Bourque and coworkers (2003) showed a combination of dietary ingredients (medium-chain triacylglycerols, phytosterols, and w-3 fatty acids), referred to as a functional oil, significantly lowers total plasma cholesterol and LDL-cholesterol levels in overweight women by 9.1 percent and 16.0 percent, respectively, compared to a beef-tallow-based diet.

R=H        :Cholesterol
R=CH₃      :Campesterol
R=C₂H₅     :β-sitosterol
R=C₂H₅,Δ²²    :Stigmasterol

SCHEME P.46 Structure of cholesterol and phytosterols. (From Lea et al., Food Chem. Toxicol., 42:771–783, 2004. With permission.)

The main mechanism responsible for the ability of free and esterified phytosterols to lower cholesterol is inhibition of cholesterol absorption (Trautwein et al., 2003). A recent survey of 9581 participants in Finland by De Jong et al. (2004) showed that of the 31 percent with high cholesterol, 19 percent used cholesterol-lowering drugs, 11 percent used phytosterol-containing spreads, while 5 percent used a combination of both therapies.

Several epidemiological and animal studies indicated that phytosterols may suppress the growth of colonic tumors (Carbin et al., 1990). A randomized, placebo-controlled, doubleblind study of 53 men found phytosterols alleviated the symptoms of prostate cancer over a three-month period (Carbin, et al. 1990). A multicentric, placebo-controlled, double-blind clinical trial involving 177 patients showed β-sitosterol as an effective option for treating benign prostatic hyperplasia. Several mechanisms were proposed based on animal-model studies in which phytosterols suppressed the metabolism and growth of the prostate by inhibiting prostatic 5α-reductase and aromatase activities (Mettlin, 1997; Awad et al., 1998). Inhibition of tumor growth was also explained by the effect of phytosterols on sphingosine metabolism in the membrane, increasing ceramide production with possible alteration of the signaltransduction pathways (Hannun and Linardic, 1993; Wollf et al., 1994). A systematic review of papers published between 1968 and 1998 on the efficacy of β-sitosterol for treating benign prostatic hyperplasia in men by Wilt et al. (1999) showed improvements in urological systems and flow measures. However, these studies were all of short duration, pointing to the need for more long-term studies to assess the efficacy and safety of β-sisterol treatment.

Possible adverse effects of high concentrations of phytosterols could result in cell fragility, particularly in patients suffering from phytosterolemia, a rare genetic disorder with very high concentrations of plasma sitosterols (Patel et al., 2004; Wang et al., 1981). Phytosterols, however, were given generally regarded as safe (GRAS) status in the U.S.A. with the Food and Drug Administration approving fat spreads containing up to 20 percent of either steryl or stanyl esters. For a more detailed discussion of phytosterols, reviews by Moghadasian (2000), Moreau et al. (2002), Tapiero et al. (2003), and Quilez et al. (2003) should be consulted.

References

Awad, A.B., Hartati, M.S., and Fink, C.S., Phytosterol feeding induces alteration in testosterone metabolism in rat tissues, J. Nutr. Biochem., 9:712–717, 1998.

Bourque, C., St-Onge, M.P., Papamandjaris, A.A., Cohn, J.S., and Jones, P.H.J., Consumption of an oil composed of median chain triacylglycerols, phytosterols, and n=3 fatty acid improves cardiovascular risk profile of overweight women, Metab., 52: 771–777, 2003.

Carbin, B.E., Larsson, B., and Lindahl, O., Treatment of benign prostatic hyperplasia with phytosterols, Br. J. Urol., 66:639–641, 1990.

Cerqueira, M.T., Fry, M.M., and Conner, W.E., The food and nutrient intakes of the Tarahumara Indians of Mexico, Am. J. Clin. Nutr., 32:905–915, 1979.

Conner, W.E., Dietary sterols: Their relationship to atherosclerosis, J. Am. Diet. Assoc., 52:202– 208, 1968.

de Jong, N., Simojoki, M., Laatikainen, T., Tapanainen, H., Valsta, L., Lahti-Koski, M., Uutela, A., and Vartjainen, E., The combined use of cholesterol-lowering drugs and cholesterol-lowering bread spreads: Health behavior data from Finland, Prev. Med., 39:849–855, 2004.

Hannun, Y.A. and Linardic, C.M., Spingomyelin breakdown products: Anti-proliferative and tumor suppressor lipids, Biochem. Biophys. Acta, 1154: 223–236, 1993.

Hicks, K.B. and Moreau, R.A., Phytosterols and phytostanols: Functional food cholesterol busters, Food Technol., 55(1):63–67, 2001.

Jones, P.J.H., MacDougall, D.E., Ntanios, F., and Vanstone, C.A., Dietary phytosterols as cholesterollowering agents in humans, Can. J. Physiol. Pharmacol., 75:217–227, 1997.

Law, M., Plant sterol and stanol margarines and health, Br. Med. J., 320:861–864, 2000.

Lea, L.J., Hepburn, P.A., Wolfreys, A.M., and Baldrick, P., Safety evaluation of phytosterol esters, part 8. Lack of genotoxicity and subchronic toxicity with phytosterol oxides, Food Chem. Toxicol., 42:771–783, 2004.

Ling, W.H. and Jones, P.J.H., Dietary phytosterols: A review of metabolism, benefits and side effects, Life Sci., 57:195–206, 1995.

Mettlin, C., Clinical oncology update: Prostate cancer, recent developments in the epidemiology of prostate cancer, Eur. J. Cancer, 33:340–347, 1997.

Miettinen, T.A., Puska, P., Gylling, H., Vanhanen, H.T., and Vartianen, E., Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population, N. Eng. J. Med., 333:1308–1312, 1995.

Moghadasian, M.H., Pharmacological properties of plant sterols: In vivo and in vitro observations, Life Sci., 67:605–615, 2000.

Moghadasian, M.H. and Frolich, J.J., Effects dietary phytosterols on cholesterol metabolism and atherosclerosis: Clinical and experimental evidence, Am. J. Med., 107:588–594, 1999.

Moreau, R.A., Whitaker, B.D., and Hicks, K.B., Phytosterols, phytostanols, and their conjugates in foods: Structural diversity, quantitative analysis, and health-promoting properties, Prog. Lipid Res., 41:457–500, 2002.

Mussner, M.-J., Pashofer, K.G., von Bergmann, K., Schwandt, P., Broedl, U., and Otto, C., Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake, Metab., 51:189–194, 2002.

Neil, H.A.W., Huxley, R.R., Hawkins, M.M., Durrington, P.N., Betteridge, D.J., Humphries, S.E., and Simon Broome Hyperlipidemia Register Group and Scientific Steering Committee, Comparison of the risk of fatal coronary heart disease in treated xanthomatous and non-xanthomatous heterozygous familial hypercholesterolaemia: A prospective registry study, Atherosclerosis, 170:73–78, 2003.

Patel, S.B., Klett, E.L., Anh, G.-S., Yu, H., Chen, J., Pandit, B., Lee, M.-H., and Salen, G., Sitosterolemia; of mice and man, Intern. Cong. Series, 1262:300–304, 2004.

Pollack, O.J. and Kritchevsky, D., Sitosterol, Monographs on Atherosclerosis, Vol. 10, Krager, Basel, New York, 1981.

Quilez, J., Garcia-Lorda, P., and Salas-Salvado, J., Potential uses and benefits of phytosterols in diet: Present situation and future directions, Clin. Nutr., 22:343–351, 2003.

Tapiero, H., Townsend, D.M., and Tew, K.D., Phytosterols in the prevention of human pathologies, Biomed. Pharmacother., 57:321–325, 2003.

Trautwein, E.A., Duchateau, G.S.M.J.E., Lin, Y., Mel’nikov, S.M., Molhuizen, H.O.F., and Ntanios, F.Y., Proposed mechanisms of cholesterol-lowering action of plant sterols, Eur. J. Lipid Sci. Technol., 105:171–185, 2003.

Wang, C., Lin, H.J., Chan, T., Salen, G., Chan, W.C. and Tse, T.F., A unique patient with coexisting cerebrotendinosus xanthomatosis and β-sitosterolemia, Am. J. Med., 71:313–319, 1981.

Wilt, TJ., MacDonald, R., and Ishani, A., Beta-sitosterol for the treatment of benign prostatic hyperplasia: A systematic review, Br. J. Urol. Int., 83:976–983, 1999.

Wollf, R.A., Dobrowsky, R.T., Bielawski, A., Obeid, L.M., and Hannun, Y.A., Role of ceramide-activated protein phosphatase in ceramide mediated signal transduction, J. Biol. Chem., 269:19607–19609, 1999.

Pine

see also Pycnogenol Pine bark is a medicinal plant used primarily for its proanthocyanidin content. Proanthocyanidins are bioflavonoids with demonstrated antioxidant properties and taken for arthritis, bruises, phlebitis, ulcers, varicose veins, and other vascular problems (Rohdewald, 2002). A pilot study by Shand et al. (2003) showed dietary supplementation with enzogenol, a flavonoid extract from pine bark, was safe and well-tolerated with a number of beneficial effects, including lowering cardiovascular risk factors. Devaraj et al. (2002) reported an increase in plasma antioxidant capacity and favorable effects on the lipid profile of human subjects treated with extract from pine bark. Pine bark antioxidants may also be helpful in treating hypoxia from arteriosclerosis, inflammation, and cardiac or cerebral infarction (Rohdewald, 2002).

Pycnogenol, a procyanidin extracted from pine bark, is a trademarked, highly standardized extract of pine bark. Supplementation of pycnogenol to patients with conventional diabetes treatment lowered glucose levels and improved endothelial function (Liu et al., 2004). Kim et al. (2004) reported that Pinus densiflora bark extracts (out of 1400 tested plants) were the strongest inhibitors of several carbohydratehydrolyzing enzymes, with potential as an antihyperglycemic drug. In mildly hypertensive patients, pycnogenol also significantly reduced the dose of the calcium antagonist nifedipine (Liu et al., 2004).

Roseff (2002) demonstrated pycnogenol therapy improved capacitated sperm morphology and increased the function of normal sperm, suggesting a less invasive and less expensive fertility-promoting procedure. Pycnogenol also proved a useful dietary supplement for C. pavum-infected patients, affording some positive health benefits, while significantly reducing oocyst shedding (Kim and Healey, 2001).

References

Devaraj, S., Vega-Lopez, S., Kaul, N., Schonlau, F., Rohdewald, P.Nd Jialal, I., Supplementation with pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile, Lipids, 37:931–934, 2002.

Kim, Y.M., Wang, M.H., and Rhee, H.I., A novel alpha-glucosidase inhibitor from pine bark, Carbohydr. Res., 339:715–717, 2004.

Kim, H.C. and Healy, J.M., Effects of pine bark administered to immunosuppressed adult mice infected with Cryptosporidium pervum, Am. J. Chem. Med., 29:469–75, 2001.

Liu, X., Wei, J., Tan, F., Zhou, S., Wurthwein, G., and Rohdewald, P., Pycnogenol®, French maritime pine bark extract, improves endothelial function of hypertensive patients, Life Sci., 74:855–862, 2004.

Rohdewald, P., A review of the French maritime pine bark extract (Pycnogenol), an herbal medication with a diverse clinical pharmacology, Int. J. Clin. Pharm. Ther., 40:158–168, 2002.

Roseff, S.J., Improvement in sperm quality and function with French maritime pine tree bark extract, J. Reprod. Med., 47:821–824, 2002.

Shand, B., Strey, C., Scott, R., Morrison, Z., and Gieseg, S., Pilot study on the clinical effects of dietary supplementation with Enzogenol®, a flavonoid extract of pine bark and vitamin C, Phytother. Res., 17:490–494, 2003.

Pinto beans

Pinto beans are excellent sources of fiber. In addition to lowering cholesterol (Bazzano et al., 2003), their high-fiber content prevents blood-sugar levels from rising too rapidly after a meal, making pinto beans a good choice for individuals with diabetes, insulin resistance, or hypoglycemia (McIntosh and Miller, 2001). The ability of pinto beans to bind bile acids in vitro suggests that they may have important, health-promoting properties by lowering cholesterol and the risk of coronary heart disease (Kahlon and Woodruff, 2002).

Marzo and coworkers (2002) showed extrusion cooking significantly (p<0.01) decreased the antinutrients, phytic acid, condensed tannins, α-amylase inhibitors, and hemagglutin-nins. Pretreatment of pinto beans by extrusion cooking improved food intake and utilization in rats by gaining body weight.

Ye and Ng (2001) isolated peptides from pinto beans with a molecular weight of 5 kDa and an N-terminal sequence similar to cowpea 10-kDa protein precursor. In addition to possessing potent antifungal activity against Botyris cinerea, Mycospaerella arachidicola, and Fusarium oxysporum, they also had mitogenic activity toward mouse splenocytes and inhibited HIV-1 reverse transcriptase.

References

Bazzano, L.A., He, J., Ogden, L.G., Loria, C.M., and Whelton, P.K., Dietary fiber intake and reduced risk of coronary heart disease in U.S. men and women: The National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study, Arch. Intern. Med., 163:1897– 1904, 2003.

Kahlon, T.S. and Woodruff, C.L., In vitro binding of bile acids by soy protein, pinto beans, black beans and wheat gluten, Food Chem., 79:425–429, 2002.

Marzo, F., Alonso, R., Urdaneta, E., Arricibita, F.J., and Ibanez, F., Nutritional quality of extruded kidney bean (Phaseolus vulgaris L. var. Pinto) and its effect on growth and skeletal muscle nitrogen fractions in rats, J. Anim. Sci., 80:875–879, 2002.

McIntosh, M. and Miller, C., A diet containing food rich in soluble and insoluble fiber improves glycemic control and reduces hyperlipidemia among patients with type 2 diabetes mellitus, Nutr. Rev., 59:52–55, 2001.

Ye, X.Y. and Ng, T.B., A new antifungal protein and a chitinase with prominent macrophagestimulating activity from seeds of Phaseolus vulgaris cv. pinto, Biochem. Biophs. Res. Commun., 290:813–819, 2002.

Piperine

Piperine is the major alkaloid component of black (Piper nigrum Linn) and long pepper (Piper longum Linn). Previous studies using animal models showed piperine inhibited several cytochrome p450-mediated pathways and phase II reactions (Atal et al., 1986; Singh et al., 1986). Rodents treated with piperine were found to have an increase in plasma levels of theophylline, phenytoin, rifampin, and propanolol (Atal et al., 1986; Velpandian et al., 2001). Rifampin and phenytoin are both substrates of the drug transporter P-glycoprotein (Schinkel et al., 1996; Schuetz et al., 1996). Bhardwaj and coworkers (2002) showed piperine inhibited both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. These researchers felt that further work was needed to clarify the impact of piperine on drug disposition in humans.

Structure of piperine. (From Bajad et al., J. Chromatogr. B., 776:245– 249, 2002. With permission.)

TABLE P.53
Effect of Piperine on the IL-1β, IL-6, GM-CSF, and TNF-α Production by B16F-10 Melanoma Cells

The anti-inflammatory effect of piperine was shown by Pradeep and Kuttan (2004) by its ability to significantly reduce proinflammatory cytokines, IL-1β, IL-6, TNF-α, and GM-CSF in B16–10 melanoma cells, as summarized in Table P.53. This was reflected by a marked inhibition of nuclear translocation of c-Fos, ATF-2, and CREB by 28.74 percent, 46.89 percent, and 64.31 percent, respectively. These results suggest that piperine prevents metastasis by targeting transcription factors.

References

Atal, C.K, Dubey, R.K., and Singh, J., Biochemical basis of enhanced drug bioavailability by piperine: Evidence that piperine is a potent inhibitor of drug metabolism, J. Pharmacol. Exp. Then, 232:258–262, 1985.

Bajad, S., Singla, A.K., and Bedi, K.L., Liquid chromatographic method for determination of piperine in rat plasma: Application to pharmacokinetics, J. Chromatogr. B., 776:245–249, 2002.

Bhardwaj, R.K., Glaeser, H., Becquemont, L., Klotz, U., Gupta, S.K., and Fromm, M.F., Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4, J. Pharmacol. Exp. Ther., 302: 645–650, 2002.

Pradeep, C.R. and Kuttan, G., Piperine is a potent inhibitor of nuclear factor-κB (NF-κB), c-Fos, CREB, ATF-2 and proinflamatory cytokine gene expression in B16F-10 melanoma cells, Inter. Immunopharmacol., 4:1795–1803, 2004.

Schinkel, A.H., Wagenaar, E., Mol, C.A.A.M., and van Deemter, L., P-glycoprotein in the blood-brain barrier in mice influences the brain penetration and pharmacological activity of many drugs, J. Clin. Invest., 97:2517–2524, 1996.

Schuetz, E.G., Schinkel, A.M., Relling, M.V., and Schuetz, J.D., P-glycoprotein: A major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans, Proc. Natl. Acad. Sci U.S.A., 93:4001–4005, 1996.

Singh, J., Dubey, R.K., and Atal, C.K., Piperinemediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea pig small intestine: Evidence that piperine lowers endogenous UDP-glucuronic acid content, J. Pharmacol. Exp. Ther., 236:488–493, 1986.

Velpandian, T., Jasuja, R., Bhardwaj, R.K., Jaiswal, J., and Gupta, S.K., Piperine in food: Interference in the pharmacokinetics of phenytoin, Eur. J. Drug. Metab. Pharmacokinet., 26:241–247, 2001.

FIGURE P.80 Acute aspirin-induced lesions. The antiulcerogenic potential of the monomeric leucocyanidin (5 mg/day), acidified aqueous extract, and active aqueous extract were derived from 5 g unripe plantain banana. Ulcer index values (Best et al., 1984) are given as the mean±SEM, with the number of repetitions in parentheses. Significant differences between treatments and control diets determined using the Wilcoxon rank sum test (*p<0.05). (From Lewis et al., J. Ethnopharmacol., 65:283–288, 1999. With permission.)

Plantain (Musa sapientum L. var. paradisiaca)

Plantain bananas, grown extensively in tropical and subtropical countries, can be eaten raw or cooked. Early studies by Elliot and Reward (1976) suggested bananas were antiulcerogenic. Subsequent work confirmed this property in plantain bananas (Best et al., 1984; Goel et al., 1989). Best and coworkers (1984) showed unripe plantain banana protected the gastric mucosa from aspirin-induced damage and that the active agent was polar and readily extracted with warm water or aqueous alcohol. Lewis and coworkers (1999) identified the antiulcerogenic agent in unripe plantain banana as the natural flavonoid, leucocyanidin. Addition of extracted and purified synthetic leucocyanidin in the diet of male Wistar rats significantly (p−<0.05) protected them from aspirin-induced lesions (Figure P.80). Unfortunately, these beneficial prophylactic effects are lost when plantains are cooked.

Leucocyanidin (3,3′,4,4′,5,7-hexahydroxyflavan). (From Lewis et al., J. Ethnopharmacol., 65:283–288, 1999. With permission.)

References

Best, R., Lewis, D.A., and Nasser, N., The antiulcerogenic activity of the unripe plantain banana, Br. J. Pharmacol., 82:107–116, 1984.

Elliot, R.C. and Reward, G.J.F., The effect of bananasupplemented diet on garlic ulcer in mice, Pharmacol. Res. Commun., 8:167–171, 1976.

Goel, R.K., Tavares, I.A., and Bennett, A., Stimulation of gastric and colonic mucosal eicosanoid synthesis by plantain banana, J. Pharm. Pharmacol., 41: 747–750, 1989.

Lewis, D.A., Fields, W.N., and Shaw, G.P., A natural flavonoid present in unripe plantain pulp (Musa sapientum L. var. paradisiaca) protects the gastric mucosa from aspirin-induced erosions, J. Ethnopharmacol., 65:283–288, 1999.

Platycodon (Platycodon grandiflorum)

Platycodon is an essential herb and a favored ingredient in Chinese medicine. The roots of Plactycodon grandiflorum have been used as a food or as a traditional oriental medicine for treating bronchitis, asthma, pulmonary tuberculosis, hyperlipidemia, diabetes, and inflammatory diseases (Takagi and Lee, 1972; Lee, 1973). Subsequent studies by Nagao et al. (1986) identified its immunopharmacological properties, while others identified some active compounds, including saponins (Ishii et al., 1984) and triterpenoids (Nikaido et al., 1999). A wide variety of compounds were reported in Platycodon grandiflorum by Kim et al. (2000) that exhibited these immunopharmacological properties. Several active compounds, platycodin D (PD) and D3 (PD3) related to oleanolic acid, were isolated from P. grandiflorum roots (Tada et al., 1975; Ishii et al., 1978). Using a rabbit macrophage-like cell line, RAW 264.7 cells, Wang et al. (2004) reported both these glycosides were powerful regulators of inflammation by reducing nitric oxide and possessed antitumor activities by stimulating TNF-α synthesis or inhibiting TNF-α mRNA degradation. (See structure for Platycodon on the next page.) Yoon and coworkers (2004) showed that a polysaccharide isolated from P. grandiflorum activated macrophages in RAW 264.7 cells, mediated, in part, by mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1).

A crude petroleum-ether extract from P. grandiflorum was shown by Lee et al. (1998) to be a much stronger inhibitor of human cancer-cell growth compared to an aqueous extract. Further fractionation of this petroleum-ether extract by Lee and coworkers (2004a) separated five fractions (I-V) on a silica-gel column. The phenolic content ranged from 1.66 to 4.80 mg/g, with fraction II containing the highest level. Comparison of their antioxidant activities, based on the formation of TBA, showed that with the exception of fraction I, all other fractions were significantly different (p<0.01) from the control (Figure P.81). Fraction II was the next most effective antioxidant after BHA, with fractions II-IV all exhibiting greater antioxidant activity than α-tocopherol. These data strongly correlated with antioxidant measurements using the ferric-thiocyanate test in which fraction II also proved to be the strongest antioxidant. Using the DPPH free-radical-scavenging test also confirmed FII to be the most potent DPPH scavenger when present at 100 and 200 mg/mL, followed by FIII. A comparison of their cytotoxicity using three human cancer lines, HT-29, HepG2, and HRT-18, showed fraction III was the most potent inhibitor. Further work by Lee et al. (2004b) identified coniferyl alcoholic esters of palmitic and oleic acids in fraction II, which may account for its antioxidant properties.

FIGURE P.81 Absorbance at 532 nm of the fractions (F1–V) from P. grandiflorum extract by TBA method compared with BHA and α-tocopherol. (From Lee et al., J. Ethnopharmacol., 93:409–415, 2004a. With permission.)

Platycodon D and platycodon D3. (Wang et al, Int. Immunopharmacol., 4:1039–1049, 2004. With permission.)

References

Ishii, H., Tori, T., Tozyo, T., and Yoshimura, Y., Structures of polgalacin D and D2, platycodon D determined by 13C nuclear magnetic resonance spectroscopy, Chem. Pharm. Bull., 26:674–677, 1978.

Ishii, H., Tori, K., Tozyo, T., and Yoshimura, Y., Saponins from roots of Platycodon grandiflorum, part 2, isolation and structure of new triterpene glycosides, J. Chem. Soc. Perkin. Trans., 1:661– 668, 1984.

Kim, K., Seo, E., Lee, Y-C., Lee, T-K., Cho, Y-W., Ezaki, O., and Kim, C-H., Effect of dietary Platycodon grandiflorum on improvement of insulin resistance in obese Zucker rats, J. Nutr. Biochem., 11: 420–424, 2000.

Lee, E.B., Pharmacological studies on Platycodon grandiflorum A. DC, IV, a comparison of experimental pharmacological effects of crude platycodin with clinical indications of Platycodi radix, Yakugaku Zasshi, 93:1188–1194, 1973.

Lee, J.Y., Hwang, W.I., and Lim, S.T., Effect of Platycodon grandiflorum extract on cancer cell lines, Korean J. Food Sci. Technol., 30:13–21, 1998.

Lee, J.Y., Hwang, W.I., and Lim, S.T., and anticancer activities of organic extracts from Platycodon grandiflorum A. De Candolle roots, J. Ethnopharmacol., 93:409–415, 2004a.

Lee, J-N., Yoon, J-Y., Kim, C-T., and Lim, S-T., Antioxidant activity of phenylpropanoid esters isolated and identified from Platycodon grandiflorum A.DC, Phytochemistry, 63:3033–3039, 2004b.

Nagao, T., Matsuda, H., Namba, K., and Kubo, M., Immune pharmacological studies on platicodi radix (II): Antitumor activity of insulin from platicodi radix, Shoykagaku Zasshi, J. Pharm. Soc. Jpn., 40: 375–380, 1986.

Nikaido, T., Koike, K., Mitsunaga, K., and Sacki, T., Two new triterpenoid saponins from Platycodon grandiflorum, Chem. Pharm. Bull., 47:903–904, 1999.

Tada, A., Kaneiwa, Y., Shoji, J., and Shibata, S., Studies on the saponins of the roots of Platycodon grandiflorum A. DC CANDOLLE I: Isolation and structure of Platycodon-D, Chem. Pharm. Bull., 23: 2965–2972, 1975.

Takagi, K. and Lee, E.B., Pharmacological studies on Platycodon grandiflorum A. DC, activities of crude platycodin on respiratory and circulatory systems and its pharmacological activities, Yakugaku Zasshi, 92:969–973, 1972.

Wang, C., Schuller Levis, G.B., Lee, E.B., Levis, W.R., Lee, D.W., Kim, B.S., Park, S.Y., and Park, E., Platycodin D and D3 isolated from the root of Platycodon gradiflorum modulate the production of nitric oxide and secretion of TNF-α in activated RAW 264.7 cells, Int. Immunopharmacol., 4:1039–1049, 2004.

Yoon, Y.D., Kang, J.S., Han, S.B., Park, S.-K., Lee, H.S., Kang, J.S., and Kim, H.M., Activation of mitogen-activated protein kinases and AP-1 by polysaccharide isolated from the radix of Platycodon gradiflorum in RAW 264.7 cells, Int. Immunophar-macol., 4:1477–1487, 2004.

Polydextrose

Polydextrose, a nondigestible polysaccharide, is prepared by bulk-melt polycondensation of glucose and sorbitol, together with small amounts of food-grade acid in vacuo (Flood et al, 2004). The overall product resulting from this random polymerization is a polymer with an average degree of polymerization of 12 with 1,6 glucosidic bonds predominating (Scheme P.47). It was approved as an additive by the FDA in 1982 and is used as a low-calorie bulking agent, replacing sugar in reduced-calorie foods (Mitchell et al., 2001). Polydextrose is often referred to as a resistant oligosaccharide or resistant polysaccharide. As a dietary fiber, it is fermented in the lower gastrointestine, producing short-chain fatty acids (SCFA), fecal bulking, reduced transit time, and glucose homeostasis (Pfizer, Inc., 1978).

Studies on the physiological effects of dietary polydextrose found it increased calcium absorption (Hara et al., 2000) and retarded lipid transport into the lymph (Ogata et al, 1997). Ishizuka and coworkers (2003) showed ingestion of polydextrose (30 mg/kg) significantly (p<0.05) suppressed formation of aberrant crypt foci (ACF) in the rat colorectum induced by 1,2-dimethylhydrazine (DMH) compared to the fiber-free diet. The earlier the animals were started on polydextrose, the more effective was the treatment in suppressing ACF development (Table P.54).

Flood and coworkers (2004) showed polydextrose was well tolerated and unlikely to induce diarrhea in adults taking less than 50 g per day. The mean laxative threshold dose for polydextrose (90 g/d or 1.3 g/kg bw) was higher than almost all of the low-caloric carbohydrates on the market.

SCHEME P.47 A representative structure for polydextrose. (From Craig et al., Cereal Foods World, 43:370–375, 1998. With permission.)

TABLE P.54
Effect of Polydextrose Ingestion on the Number of ACF in the Rat Colorectum Induced by DMH at Five Weeks After Injection^1,2

References

Anonymous, Polydextrose Food Additive Petition #9A3441, Zpfizer, 1978.

Craig, S.A., Holden, J.F., Auerbach, M.H., and Frier, H.I., Polydextrose as soluble fiber: Physiological and analytical aspects, Cereal Foods World, 43:370–375, 1998.

Flood, M.T., Auerbach, M.H., and Craig, S.A.S., A review of the clinical toleration studies of polydextrose in foods, Food Chem. Toxicol., 42:1531–1542, 2004.

Hara, H., Suzuki, T., and Kasai, T., Ingestion of the soluble dietary fibre polydextrose, increases calcium absorption and bone mineralization in normal and total-gastrectomized rats, Br. J. Nutr., 84:655–661, 2000.

Ishizuka, S., Nagai, T., and Hara, H., Reduction of aberrant crypt foci by ingestion of polydextrose in rat colorectum, Nutr. Res., 23:117–123, 2003.

Mitchell, H., Auerbach, M.H., and Moppett, F.K., Polydextrose, in Alternative Sweeteners, 3rd edition, Nabors, L.O., Ed., Marcel Dekker, New York, 2001, chap. 26, pp. 499–518.

Ogata, S., Fujimoto, K., Iwakiri, R., Matsunaga, C., Ogawa, Y., Koyama, T., and Sakai, T., Effect of polydextrose on absorption of triglyceride and cholesterol in mesenteric lymph-fistula rats, Proc. Soc. Exp. Biol. Med., 215:53–58, 1997.

Pfizer Inc., Polydextrose food addtive petition. New York: Pfizer Inc. (FDA petition 9A344), 1978.

Pomegranate (Punica granatum)

The peel of pomegranates was reported to contain large amounts of polyphenols and is used in tinctures, cosmetics, therapeutic formulations, and food recipes (Ben Nasr et al., 1996). The juice of pomegranates was also a rich source of antioxidants (Gil et al., 2000), which accounted for its antiatherogenic effects in humans and animals (Aviram et al., 2000). Using in vitro models, Singh et al. (2002) determined the antioxidant activity of ethyl acetate, methanol, and water extracts of pomegranate peels and seeds. Of these, the methanol extract exhibited the greatest antioxidant activity. A recent study by Negi and coworkers (2003) prepared dried powders from peeled pomegranates by Soxhlet extraction with ethyl acetate, acetone, methanol, and water and tested each one for antioxidant and antimutagenic activities. All peel extracts showed potent antioxidant capacity, with the water extract being the lowest. With respect to their antimutagenicity using the Ames test, the order of activity was water extract > acetone > ethyl acetate > methanol. These results suggested pomegranate-peel extracts have considerable potential as nutraceuticals. This was confirmed by Aviram and coworkers (2004) who fed pomegranate juice for a year to 10 patients suffering from carotidartery stenosis, with five of them continuing on for up to three years. In contrast to patients with severe carotid-artery stenosis not consuming pomegranate juice, there was a significant (p< 0.01) decrease in the mean intima-media thickness of the left and right common carotid arteries of 13 percent, 22 percent, 26 percent, and 35 percent after 3, 6, 9, and 12 months consumption of pomegranate juice compared to a 9 percent increase for the control (Figure P.82). A significant (p<0.05) decrease in systolic pressure also accompanied pomegranate-juice consumption, with a reduction of 7 percent, 11 percent, 10 percent, 10 percent, and 12 percent after 1, 3, 6, 9, and 12 months of consumption. No significant changes were observed on the patients’ diastolic pressure.

FIGURE P.82 The effect of pomegranate-juice consumption by patients with carotid-artery stenosis on carotid mean intima-media thickness (IMT). Ten patients with severe carotid-artery stenosis were supplemented with pomegranate juice for up to one year, with carotid IMT measured in the patients’ left and right carotid arteries before treatment (Baseline) and during pomegranate-juice consumption. (From Aviram et al., Clin. Nutr., 23:423–433, 2004. With permission.)

Kulkarni et al. (2004) recently isolated and characterized the phenolic compound, punicalagin, from the methanol extract of the pith and carpellary membrane of pomegranate fruit. This compound exhibited potent DPH radical-scavenging activity by donating electrons to free radicals. They suggested that the waste material (pith and carpellary membrane) in pomegranate could be a viable source of this natural and potent antioxidant.

Punicalagin. (From Kularni et al., Food Chem., 87:551–557, 2004. With permission.)

References

Aviram, M., Dornfeld, L., Rosenblat, M., Volkova, N., Kaplan, M., Coleman, R., Hayek, T., Presser, D., and Fuhrman, B., Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and atherosclerotic apolipoprotein E-deficient mice, Am. J. Clin. Nutr., 71:1062–1076, 2000.

Aviram, M., Rosenblat, M., Gaitini, D., Nitecki, S., Hoffman, A., Dornfield, L., Volkova, N., Presser, D., Attias, J., Liker, H., and Hayek, T., Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation, Clin. Nutr., 23:423–433, 2004.

Ben Nasr, C.B., Ayed, N., and Metche, M., Quantitative determination of the polyphenolic content of pomegranate peel, Z. Lebensm Unters Forsch, 203: 374–378, 1996.

Gil, M.I., Tomas-Barberan, F.A., Hess-Pierce, B., Holcroft, D.M., and Kader, A.A., Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing, J. Agric. Food Chem., 48:4581–4589, 2000.

Kulkarni, A.P., Aradhya, S.M., and Divakar, S., Isolation and identification of a radical scavenging anti-oxidant-punicalagin from pith and carpellary membrane of pomegranate fruit, Food Chem., 87: 551–557, 2004.

Negi, P.S., Jayaprakasha, G.K., and Jena, B.S., Anti-oxidant and antimutagenic activities of pomegranate peel extracts, Food Chem., 80:393–397, 2003.

Singh, R.P., Murthy, K.N.C., and Jayaprakasha, G.K., Studies on the antioxidant activity of pomegranate (Punica granatum) peel and seed extract using in vitro models, J. Agric. Food Chem., 50:81–86, 2002.

Poppy

The opium poppy, Papaver somniferum, is one of man’s oldest medicinal plants. Today, opium poppy is a commercial source of narcotic analgesics, morphine and codeine. Along with two morphinans, opium poppy produces approximately 80 alkaloids belonging to various tetrahydrobenzylisoquinoline derivatives. These morphinan alkaloids accumulate in the latex of opium poppy (Weid et al., 2004).

Originally, opium poppies were grown for the pharmaceutical industry for morphine production. However, morphine-free varieties were developed for baking and confectionery purposes. Poppy seeds contain up to 50 percent of a high-quality, semi-drying oil, containing 72 percent linoleic acid, used in artists’ paints (Table P.55).

Raw opium contains approximately 25 different alkaloids by weight, depending on the variety. The major alkaloids are morphine (4–21 percent), codeine (0.8–2.5 percent), thebaine (0.5–2.0 percent), papaverine (0.5–2.5 percent), noscapine (0.5–2.5 percent), and meconic acid (3–5 percent). Interaction of poppy alkaloid opioids with endogenous opiate receptors in the brain is recognized by clinical pharmacologists for such plants with a long-established medicinal use (Perry et al., 1999). Poppy seeds from Papaver somniferum L. were found to contain total morphine (free and bound) in the range of 58.4 to 52.2 micrograms/g of seed and total codeine (free and bound) in the range of 28.4 to 54.1 micrograms/g of seed (Lo and Chua, 1992). Thus, a positive result for morphine in oral fluid may be due to ingestion of poppy seeds (Rohrig and Moore, 2003). However, poppy seeds can also induce immediate-type allergic reactions, ranging from mild, local symptoms to severe anaphylactic reactions, by cross-reacting with other plant-derived allergens (Jensen-Jarolim et al., 1999).

TABLE P.55
Fatty-Acid Composition of Poppy Oil

References

Jensen-Jarolim, E., Gerstmayer, G., Kraft, D., Scheiner, O., Ebner, H., and Ebner, C., Serological characterization of allergens in poppy seeds, Clin. Exp. Allergy, 29:1075–1079, 1999.

Lo, D.S. and Chua, T.H., Poppy seeds: Implications of consumption, Med. Sci. Law, 32:296–302, 1992. Perry, E.K., Pickering, A.T., Wang, W.W., Houghton, P.J., and Perry, N.S., Medicinal plants and Alzheimer’s disease from ethnobotany to phytotherapy, J. Pharm. Pharmacol., 51:527–534, 1999.

Rohrig, T.P. and Moore, C., The determination of morphine in urine and oral fluid following ingestion of poppy seeds, J. Anal. Toxicol., 27:449–452, 2003.

Serpico, M. and White, R., Oil, fat, and wax in Ancient Egyptian Materials and Technology, P. Nicholson and I. Shaw, Eds., Cambridge University Press, Cambridge, UK., pp. 390–429, 2000.

Weid, M., Ziegler, J., and Kutchan, T.M., The roles of latex and the vascular bundle in morphine biosynthesis in the opium poppy, Papaver somniferum, Proc. Natl. Acad. Sci. U.S.A., 101:13957–13962, 2004.

Pot marigold

Pot marigold (Calendula officinalis) is an annual herb with many pharmacological properties. It is used to treat skin disorders and as a bactericide, antiseptic, and anti-inflammatory. The butanol extract of Calendula officinalis was shown to have significant radical-scavenging activity (Cordova et al., 2002), which may explain part of its therapeutic efficacy. Dichloromethane extracts of its flowers were shown to contain eight known bioactive triterpenoid monoesters (Neukirch et al., 2004). Faradiol 3-O-laurate, palmitate, and myristate were identified as the major anti-inflammatory triterpenoid esters in the flower heads of Calendula officinalis (Hamburger et al., 2003).

The main carotenoids found in the petals and pollens of Calendula officinalis were flavoxanthin and astaxanthin, while the stems and leaves contained mostly lutein and β-carotene (Bako et al., 2002). Calendasaponins A, B, C, and D, ionone glucosides (officinosides A and B), and sesquiterpene oligoglycosides (officinosides C and D) were all isolated from the flowers of Egyptian Calendula officinalis exhibiting hypoglycemic, gastric emptying inhibitory, and gastroprotective effects (Yoshikawa et al., 2001).

Perez-Carreon et al. (2002) demonstrated the chemopreventive properties of Calendula officinalis extracts by their antigenotoxic effects on rat liver cell cultures treated with diethylnitrosamine. At higher concentrations, however, they proved genotoxic. In a phase III randomized trial, Pommier et al. (2004) found Calendula officinalis was an effective, nonsteroid topical agent for preventing acute dermatitis during adjuvant radiotherapy for breast carcinoma compared to the drug trolamine. They proposed its use for patients undergoing postoperative irradiation for breast cancer.

References

Bako, E., Deli, J., and Toth, G., HPLC study on the carotenoid composition of Calendula products, J. Biochem. Biophys. Methods, 53:241–250, 2002.

Cordova, C.A., Siqueira, I.R., Netto, C.A., Yunes, R.A., Volpato, A.M., Cechinel, Filho, V., Curi-Pedrosa, R., and Creczynski-Pasa, T.B., Protective properties of butanoilic extract of the Calendula officinalis L. (marigold) against lipid peroxidation of rat liver microsomes and action as free radical scavenger, Redox Rep., 7:95–102, 2002.

Hamburger, M., Adler, S., Baumann, D., Forg, A., and Weinreich, B., Preparative purification of the major anti-inflammatory triterpenoid esters from marigold (Calendula officinalis), Fitoterapia, 74: 328–338, 2003.

Neukirch, H., D’Ambrosio, M., Dalla Via, J., and Guerriero, A., Simultaneous quantitative determination of eight triterpenoid monoesters from flowers of 10 varieties of Calendula officinalis L. and characterization of a new triterpenoid monoester, Phytochem. Anal., 15:30–35, 2004.

Perez-Carreon, J.I., Cruz-Jimenez, G., Licea-Vega, J.A., Arce Popoca, E., Fattel Fazenda, S., and VillaTrevino, S., Genotoxic and anti-genotoxic properties of Calendula officinalis extracts in rat liver cultures treated with diethylnitrosamine, Toxicol. In Vitro, 16: 253–258, 2002.

Pommier, P., Gomez, F., Sunyach, M.P., D’Hombres, A., Carrie, C., and Montbarbon, X., Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer, J. Clin. Oncol., 22: 1447–1453, 2004.

Yoshikawa, M., Murakami, T., Kishi, A., Kageura, T., and Matsuda, H., Medicinal flowers III. Marigold. (1): hypoglycemic, gastric emptying inhibitory, and gastroprotective principles and new oleanane-type triterpene oligoglycosides, calendasaponins A, B. C, and D from Egyptian Calendula officinalis, Chem. Pharm. Bull., 49:863–870, 2001.

Potato

Antioxidant activity in potatoes is supported by the findings of free and bound phenolics (Chu et al., 2002). In particular, potato peel, a waste product from potato processing, was found to be rich in phenolic acids (Lisinska and Leszczynski, 1987) and later shown to be a source of antioxidants in food systems (Rodriguez et al., 1994). Rehman et al. (2004) recently examined a petroleum-ether extract from potato peels that exhibited strong antioxidant activity and enhanced the shelf life of soybean oil. The free-radical-scavenging activity of a freeze-dried aqueous extract of potato peel was confirmed by Singh and Ranjini (2004) using 1,1-diphenyl-2-picrylhydrazine) (DPPH). They also reported it strongly inhibited lipid peroxidation of rat liver homogenates induced by the FeCl₂-H₂O₂ system. Further work is needed to ensure the safety and efficacy of the antioxidants from potatoes and potato peels in relation to their potential as sources of nutraceuticals.

Morita et al. (1997) reported lower serum total-cholesterol concentrations in rats fed potato proteins compared to those fed casein. Schafer et al. (2003) later showed potatoes, as a carbohydrate source, elicited significantly better glycemic and insulinemic responses in patients with type 2 diabetes compared to dried peas.

References

Chu, Y-F., Sun, J., Wu, X., and Liu, R.H., Antioxidant and antiproliferative activities of common vegetables, J. Agric. Food Chem., 50:6910–6916, 2002.

Lisinska, G. and Leszczynski, W., Potato tubers as raw materials for processing and nutrition, in Potato Science and Technology, Lisinska, G., and Leszczynski, W., Eds., Elsevier Applied Science, London, 1987, chap. 2, pp. 34–38.

Morita, T., Oh-hashi, A., Takei, K., Ikai, M., Kasaoka, S., and Kiriyama, S., Cholesterol-lowering effects of soybean, potato and rice proteins on their low methionine contents in rats fed a cholesterol-free purified diet, J. Nutr., 127:470–477, 1997.

Rehman, Z.-U., Habib, F., and Shah, W.H., Utilization of potato peels extract as a natural antioxidant in soybean oil, Food Chem., 85:215–220, 2004.

Rodriguez de Sotillo, D., Hadley, M., and Holm, E.T., Potato peel waste: Stability and antioxidant activity of freeze-dried extract, J. Food Sci., 59: 1031–1033, 1994.

Schafer, G., Schenck, U., Ritzel, U., Ramadori, G., and Leonhardt, U., Comparison of the effects of dried peas with those of potatoes in mixed meals on post-prandial glucose and insulin concentrations in patients with type 2 diabetes, Am. J. Clin. Nutr., 78: 99–103, 2003.

Singh, N. and Rajini, P.S., Free radical scavenging activity of an aqueous extract of potato peel, Food Chem., 85:611–616, 2004.

Prebiotics

see also Acacia gum, Arabinoxylan, Fructooligosaccharides, and Inulin Prebiotics are oligosaccharides that promote the growth of beneficial bacteria in the GI tract. These include inulin-type fructans, which include native inulin, hydrolyzed inulin, or oligofructose and synthetic fructooligosaccharides (Roberfroid, 1998; Roberfroid et al., 1998).

Human milk oligosaccharides represent the first prebiotics in humans, as they are only partially digested in the small intestine. Once they reach the colon, they selectively stimulate the development of the bifidogenic flora (Coppa et al., 2004). A bovine-milk formula supplemented with a prebiotic mixture of galactooligosaccharides and fructooligosaccharides can stimulate an intestinal flora, similar to that of breast-fed infants. Several biota, whose growth is enhanced by this prebiotic mixture, represent important factors in the postnatal development of the immune system (Boehm et al., 2004).

Dietary modulation of the gut microflora by prebiotics is designed to improve health by stimulating the numbers and activities of the bifidobacteria and lactobacilli. Having an “optimal” gut microflora can increase resistance to pathogenic bacteria, lower blood ammonia, increase stimulation of the immune response, and reduce the risk of cancer (Manning and Gibson, 2004). Thus, the physiological consequences of prebiotic consumption are evaluated in terms of potential to reduce risk for disease. Most research has been done with β(2–1) fructans as an example of prebiotics. These results are relevant in the fields of gut function, lipid metabolism, mineral absorption, bone formation, immunology, and cancer (Van Loo, 2004).

References

Boehm, G., Jelinek, J., Stahl, B., van Laere, K., Knol, J., Fanaro, S., Moro, G., and Vigi, V., Prebiotics in infant formulas, J. Clin. Gastroenterol., 38(Suppl. 6): S76–S79, 2004.

Coppa, G.V., Bruni, S., Morelli, L., Soldi, S., and Gabrielli, O., The first prebiotics in humans: Human milk oligosaccharides, J. Clin. Gastroenterol., 38(Suppl. 6):S80–S83, 2004.

Manning, T.S. and Gibson, R.R., Prebiotics, Best Pract. Res. Clin. Gastroenterol., 18:287–298, 2004.

Roberfroid, M.B., Dietary fructans, Ann. Rev. Nutr., 18:117–143, 1998.

Roberfroid, M.B., Van Loo, J.A.E., and Gibson, G.R., The bifidogenic nature of chicory inulin and its hydrolyzed products, J. Nutr., 128:11–19, 1998.

Van Loo, J.A., Prebiotics promote good health: The basis, the potential, and the emerging evidence, J. Clin. Gastroenterol., 38(Suppl. 6):S70–S75, 2004.

Probiotics

Probiotics are bacteria that keep disease-causing organisms in check. For example, Lactobacillus acidophilus is added to yogurt while Lactobacillus reuteri and Lactobacillus bifidus also promote health. Probiotics are viable microbial food ingredients that have a beneficial effect on the intestinal tract of their host (Salimen et al., 1998). Most probiotics are lactobacilli and bifidobacteria, presently consumed almost exclusively as fermented dairy products, such as yogurts or freeze-dried cultures. These probiotics survive the digestive process and become established in the large bowel with recognized benefits (Sanders, 1993; Marteau and Rambaud, 1993; Salimen et al., 1996). Studies have shown probiotics may be effective in reducing diarrhea (Isolauri et al., 1991; Corthier, 1997; Allen et al., 2004). Other studies suggest probiotics could help in managing clinical inflammatory-bowel disease (Fedorak and Madsen, 2004) and in treating functional abdominal bloating (Di Stefano et al., 2004).

Steatohepatitis is recognized as the leading cause of cryptogenic cirrhosis, although the pathogenesis of this disease is not fully understood. Nevertheless, among various factors implicated, intestinal bacterial overgrowth may be involved. Thus, probiotic treatment may be beneficial (Nardone and Rocco, 2004).

Studies examining the use of probiotics in food allergy, atopic dermatitis, and in the primary prevention of atopy found probiotic therapy alleviated allergic inflammation by controlling symptoms and reducing local and systemic inflammatory markers (Miraglia del Giudice and De Luca, 2004). Probiotics may also improve lactose absorption and Helicobacter pylori eradication and constipation. In animal models with colorectal cancer, treatment with probiotics reduces the prevalence of this disease, while in humans, the amount of genotoxic substances in the feces are reduced (Goossens et al., 2003).

In summary, the potential benefits of probiotics include: adherence to cells; exclusion or reduction of pathogenic adherence; production of acids, hydrogen peroxide, and bacteriocins antagonistic to pathogen growth; safe, noninvasive, noncarcinogenic, and nonpathogenic characteristics; and congregate to form a more balanced intestinal flora (Otles et al., 2003).

References

Allen, S.J., Okobo, B., Martinez, E., Gregorio, G., and Dans, L.F., Probiotics for treating infectious diarrhoea, Cochrane Database Syt. Rev., CD003048, 2004.

Corthier, G., Antibiotic-associated diarrhoea and pseudomembranous colitis, in Probiotics 2: Applications and Practical Aspects, Fuller, R., Ed., Chapman & Hall, London, 1997, pp. 40–64.

Di Stefano, M., Miceli, E., Armellini, E., Missanelli, A., and Corazza, G.R., Probiotics and functional abdominal bloating, J. Clin. Gastroenterol., 38(Suppl. 6):S102–S103, 2004.

Fedorak, R.N. and Madsen, K.L., Probiotics and the management of inflammatory bowel disease, Inflamm. Bowel Dis., 10:286–299, 2004.

Goossens, D., Jonkers, D., Stobberingh, E., van den Bogaard, A., Russel, M., and Stockbrugger, R., Probiotics in gastroenterology: Indications and future perspectives, Scand. J. Gastroenterol., 38(Supp. 239): 15–23, 2003.

Isolauri, E., Juntunen, M., Rautanen, T., Sillanaukee, P., and Koivula, T., A human Lactobacillus strain (Lactobacillus casei strain CG) promotes recovery of acute diarrhea in children, Pediatrics, 88:90–97, 1991.

Marteau, P. and Rambaud, J.C., Potential of using lactic acid bacteria for therapy and immunomodulation in man, FEMS Microbiol. Rev., 12:202–220, 1993.

Miraglia del Giudice, M. and De Luca, M.G., The role of probiotics in the clinical management of food allergy and atopic dermatitis, J. Clin. Gastroenterol., 38:S84-S85, 2004.

Nardone, G. and Rocco, A., Probiotics: A potential target for the prevention and treatment of steatohepatitis, J. Clin. Gastroenterol., 38:S121–S122, 2004.

Otles, S., Cagindi, O., and Akcicek, E., Probiotics and health, Asian Pac. J. Cancer Prev., 4:369– 372, 2003.

Salimen, S., Bouley, C., Boutron-Ruault, M.C., Cummings, J.H., Franck, A., Gibson, G.R., Isolauri, E., Moreau, M-C., Roberfroid, M., and Rowlands, J., Functional food science and gastrointestinal physiology and function, Br. J. Nutr., 80 (Suppl. 1): S147–171, 1988.

Salimen, S., Isolauri, E., and Salimen, E., Clinical uses of probiotics for stabilizing the gut micosal barrier: Successful strains and future challenges, Antonie Van Leeuwenhok, 70:347–358, 1996.

Sanders, M.E., Summary of the conclusions from a consensus panel of experts on health attributes of lactic cultures: significance to fluid milk products containing cultures, J. Dairy Sci., 76:1819– 1828, 1993.

Propolis or bee glue

Propolis or bee glue, a resinous plant material collected by honeybees from the buds and bark of certain plants and trees, may serve as a defense for their hives (Ghisalberti, 1979). A number of health benefits have been ascribed to propolis, including anticancer (Matsuno, 1995), antimicrobial (Koo et al., 2000), anti-inflammatory, and antibiotic (Bianchini and Bendendo, 1998) properties. Propolis contains many different types of flavonoids and cinnamic-acid derivatives, some of which are known antitumor agents. One of the components identified by Matsuno et al. (1997) was artepillin C (3,5-diprenyl-4-hydroxycinnamic acid). This compound was shown to reduce tumors in experimental-animal models (Kimoto et al., 2000, 2001). The antimutagenic properties of an ethanol extract of bee glue or propolis (EEGB) against a number of environmental mutagens was demonstrated by Jeng and coworkers (2000). These researchers reported EEGB suppressed the mutagenicity of two direct mutagens, 4-nitro-O-phenylenediamine (4-NO) and 1-nitropyrene (1NP), and two indirect mutagens, 2-amino-3-methylimidazo[4.5-f] quinoline (IQ) and benzo[α]pyrene (B[a]P in a dose-dependent manner. Sugimoto et al. (2003) recently examined the inhibitory effects of propolis granular A.P.C., an extract containing more than 35.8 μg artepillin C/g, on female A/J mice lung tumors induced by 4-(methymitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most potent carcinogens among tobacco-specific nitrosamines. While lungtumor incidence was not affected by propolis, tumor multiplicity was significantly (p<0.01) reduced by 72 percent. No adverse effects were observed from propolis granular A.P.C., suggesting possible clinical applications. Further research is warranted to substantiate the role of artepillin C and other components in the antitumor properties of propolis A.P.C.

Artepillin C. (From Uto et al., J. Org. Chem., 67:2355–2357, 2002.)

TABLE P.56
Lipid Levels in Serum of Rats Given Alcohol and Alcohol+Propolis for 15 Days

Kolankaya and coworkers (2002) reported that Turkish Castenea saliva propolis exerted a protective effect against degenerative diseases and alcohol-induced oxidative stress. In the presence of propolis treatment, the alcohol-induced oxidative stressed male rats had increased HDL and decreased the LDL levels compared to the alcohol-induced stressed animals (Table P.56).

In addition, the activity of LDH enzyme increased in the presence of propolis compared to the control. These researchers suggested that propolis exerted its protective effect against degenerative diseases through its protection against free radicals.

Matsui and coworkers (2004) showed a single, oral administration of propolis extract to Sprague-Dawley rats had a potent antihyperglycemic effect, with a significant reduction of 38 percent at a dose of 20 mg/kg compared to the control. Among the active compounds isolated from this fraction, 3,4,5-tri-O-caffeoylquinic acid, proved to be most prominent.

References

Bianchini, L. and Bedendo, I.P., Antibiotic effect of propolis against plant pathogenic bacteria, Scienta Agricola, 55:149–152, 1998.

Ghisalberti, E.L., Propolis: A review, Bee World, 60: 59–84, 1979.

Jeng, S.N., Shih, M.K., Kao, C.M., Liu, T.Z., and Chen, S.C., Antimutagenicity of ethanol extracts of bee glue against environmental mutagens, Food Chem. Toxicol., 38:893–897, 2000.

Kimoto, T., Koya, S., Hino, K., Yamamoto, Y., Nomura, Y., Micallef, M.J., Hanaya, T., Arai, S., Ikeda, M., and Kurimoto, M., Renal carcinogenesis induced by ferric nitriloacetate in mice, and protection from its Brazilian propolis and artepillin C, Pathol Int., 50:670–680, 2000.

Kimoto, T., Koya-Miyata, S., Hino, K., Micallef, M.J., Hanaya, T., Arai, S., Ikeda, M., and Kurimoto, M., Pulmonary carcinogenesis induced by ferric nitriloacetate in mice and protection from it by Brazilian propolis and artepillin C, Virchows Arch., 438: 259–270, 2001.

Kolankaya, D., Selmanoglu, G., Sorkun, K., and Salih, B., Protective effects of Turkish propolis on alcohol-induced serum lipid changes and liver injury in male rats, Food Chem., 78:213–217, 2002.

Koo, H., Gomes, B.P.F.A., Rosalen, P.L., Ambrosano, G.M.B., Park, Y.K., and Cury, J.A., In vitro antimicrobial activity of propolis and Arnica montana against oral pathogens, Arch. Oral Biol., 45: 141–148, 2000.

Matsui, T., Ebuchi, S., Fujise, T., Abesundara, K.J., Doi, S., Yamada, H., and Matsumoto, K., Strong antihyperglycemic effects of water-soluble fraction from Brazilian propolis and its bioactive constituent, 3,4,5-tri-O-caffeoylquinic acid, Biol. Pharm. Bull., 27:1797–1803, 2004.

Matsuno, T., A new clerodane diterpenoid isolated from propolis, Z. Naturforsch., 50c:93–97, 1995.

Matsuno, T., Kung, S.K., Matsumoto, Y., Saito, M., and Morikawa, J., Preferential cytoxicity to tumor cells of 3.5-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated from propolis, Anticancer Res., 17:3565–3568, 1997.

Nagai, T., Inoue, R., Inoue, H., and Suzuki, N., Preparation and antioxidant properties of water extract of propolis, Food Chem., 80:29–33, 2003.

Pascual, C., Gonzalez, R., and Torricella, R.G., Scavenging action of propolis extract against oxygen radicals, J. Ethnopharmacol., 41:9–13, 1994. Sugimoto, Y., Iba, Y., Kayasuga, R., Kirino, Y., Nishiga, M., Hossen, M.A., Okihara, K.,

Sugimoto, H., Yamada, H., and Kamei, C., Inhibitory effects of propolis granular A.P.C on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A.J. mice, Cancer Lett., 193:155–159, 2003.

Uto, Y., Hirata, A., Fujita, T., Takubo, S., Nagasawa, H., and Hitoshi, H., First total synthesis of artepillin C established by o,o′-diprenylation of p-halophenols in water, J. Org. Chem., 67:2355–2357, 2002.

Walker, P. and Crane, E., Constituents of propolis, Apidologie, 18:327–334, 1987.

Prostaglandins

Prostaglandins are bioactive lipids produced from arachidonic acid. They are found in many vertebrate tissues, where they act as messengers involved in reproduction and inflammatory response to infection. They exert an autocrine-paracrine function by attaching to specific prostanoid G protein-coupled receptors to activate intracellular signaling and gene transcription. For many years, prostaglandins were recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology, and proliferation of endometrial glands and menstruation (Sales and Jabbour, 2003). More recently, a role in reproductivetract pathology was reported, including carcinomas, menorrhagia, dysmenorrhoea, and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for them in angiogenesis, apoptosis and proliferation, tissue invasion, and metastases and immunosuppression (Martel-Pelletier et al., 2004).

Prostaglandins thus act on a variety of cells, such as vascular smooth muscle cells, causing constriction and dilation, on platelets causing aggregation or disaggregation, and on spinal neurons causing pain. Other effects can be calcium movement, hormone regulation, and cellgrowth control. Certain prostaglandins are involved with induction of labor and other reproductive processes. For example, PGE2 causes uterine contractions and has been used to induce labor. Prostaglandins are also involved in several other organs, such as the gastrointestinal tract (inhibiting acid synthesis and increasing secretion of protective mucus), increases blood flow in the kidneys, and leukotrienes, which promote constriction of bronchi associated with asthma. A recent review by Prisk and Huard (2004) examines the role of prostaglandins and their potential for therapeutic interventions.

References

Martel-Pelletier, J., Pelletier, J.P., and Fahmi, H., New insights into prostaglandin biology, J. Rheumatol., 31:14–16, 2004.

Prisk, V. and Huard, J., Muscle injuries and repair: The role of prostaglandins and inflammation, Histol. Histopathol., 18:1243–1256, 2003.

Jabbour, H.N. and Sales, K.J., Prostaglandin receptor signaling and function in human endometrial pathology, Trends Endocrinol. Metab., 15:398–404, 2004.

Protease inhibitors

see Bowman-Birk protease inhibitor and Trypsin inhibitors

Proteins

see Amaranth, Casein, Quinoa, and Soybean

Prunes

Prunes (Prunus domestica L.) are a good source of dietary fiber, as well as phenolic compounds, ascorbic acid, and carotenoids (Bravo, 1998). The dietary fiber in prunes is composed mainly of pectin (60 percent). The major components of prune powder are shown in Table P.57. Lucas et al. (2000) reported that inclusion of 25 percent prunes in the diets of ovariectomy-induced hypercholesterolemic rats prevented a rise in serum, total, and non-HDL cholesterol concentrations.

TABLE P.57
Proximate Analysis of Prune Powder

Prunes are particularly well known for their laxative action, which is explained by their high sorbitol content. They are also a good source of energy in the form of simple sugars but do not mediate a rapid rise in blood sugar, possibly because of their high fiber, fructose, and sorbitol content. The large amounts of phenolic compounds (184 mg/kg) in prunes may aid their laxative action and delay glucose absorption (Kikuzaki et al., 2004). Phenolic compounds in prunes have also been found to inhibit human LDL oxidation in vitro, and thus might serve as preventive agents against chronic diseases, such as heart disease and cancer (Kayano et al., 2003). In addition, the high potassium content of prunes (745 mg/100 g) might be beneficial for cardiovascular disease. Dried prunes are also an important source of boron, which is postulated to play a role in the prevention of osteoporosis (Stacewicz-Sapuntzakis et al., 2001).

References

Bravo, L., Polyphenols: Chemistry, dietary sources, metabolism and nutritional significance, Nutr. Rev., 56:317–333, 1998.

Kayano, S., Yamada, N.F., Suzuki, T., Ikami, T., Shioaki, K., Kikuzaki, H., Mitani, T., and Nakatani, N., Quantitative evaluation of antioxidant components in prunes (Prunus domestica L.), J. Agric. Food Chem., 51:1480–1485, 2003.

Kikuzaki, H., Kayano, S., Fukutsuka, N., Aoki, A., Kasamatsu, K., Yamasaki, Y., Mitani, T., and Nakatani, N., Abscisic acid related compounds and lignans in prunes (Prunus domestica L.) and their oxygen radical absorbance capacity (ORAC), J. Agric. Food Chem., 52:344–349, 2004.

Lucas, E.A., Juma, S., Stoecker, B.J., and Arjmandi, B.H., Prune suppresses ovariectomy-induced hypercholesterolemia in rats, J. Nutr. Biochem., 11:255–259, 2000.

Stacewicz-Sapuntzakis, M., Bowen, P.E., Hussain, E.A., Damayanti-Wood, B.I., and Farnsworth, N.R., Chemical composition and potential health effects of prunes: A functional food? Crit. Rev. Food Sci. Nutr., 41:251–286, 2001.

Pseudopterosins

Pseudopterosins are diterpeneglycosides isolated from the Caribbean sea whip Pseudopterogorgia elisabethae (Octocrallia, Cnidaria). They have been shown to possess anti-inflammatory and analgesic properties (Look et al., 1986). Pseudopterosin A, a C-9 xylose glycoside isolated from the marine gorgonian Pseudopterogorgia elisabethae, was found to be effective in reducing PMA-induced mouse-ear edema when administered topically. Mayer et al. (1998) showed it inhibited prostaglandin ER2 and leukotriene C4 production in zymosan-stimulated murine peritoneal macrophages, suggesting pseudopterosin A mediated anti-inflammatory effects by inhibiting ecosanoid release from inflammatory cells. The nonsteroidal, anti-inflammatory, and analgesic properties of pseudopterosins were shown to be greater than the industry standard drug, indomethacin. This led investigators to examine the biosynthesis and enzymology of these compounds to develop a biotechnology production method (Kohl et al., 2003). Ata and coworkers (2003) identified a number of new pseudopterosins and seco-pseudopterosins from marine gorgonian Pseudoprerogorgia elisabethae, as well as a novel hydroxyquinone, elisabethadione. The anti-inflammatory properties of the latter, however, proved more potent than either pseudopterosin A or E. Seven new pseudopterosins, P-V, were identified recently by Duque et al. (2004) from gorgonian octocoral Pseudopterogorgia elisabethae from Providencia Island in the Colombian Caribbean, as shown in Scheme P.48. However, their health-related properties still remain to be studied.

1: R₁, R₂, R₃=H 2: R₁=Ac, R₂, R₃=H ₃: R₂=Ac, R_1, R₃=H 4: R₃=Ac, R₁, R₂=H     5: R₁, R₂, R₃=H 6: R₁=Ac, R₂, R₃=H 7: R₂=Ac, R₁, R₃=H

SCHEME P.48 New pseudopterosins isolated from Pseudopterogorgia elisabethae from Providencia island, Colombian Caribbean. (From Duque et al., Tetrahedron, 60:10627–10635, 2004. With permission.)

References

Atta, A., Kerr, R.G., Moya, C.E., and Jacobs, R.S., Identification of anti-inflammatory diterpenes from the marine gorgonian Pseudopterogorgia elisabe-thae, Tetrahedron, 59:4215–4222, 2003.

Duque, C., Puyana, M., Narvaez, G., Osorno, O., Hara, N., and Fujimoto, Y., Pseudopterosins P-V, new compounds from gorgonian octocoral Pseudopterogorgia elisabethae from Providencia island, Columbian Caribbean, Tetrahedron, 60: 10627–10635, 2004.

Kohl, A.C., Ata, A., and Kerr, R.G., Pseudopterosin biosynthesis—pathway elucidation, enzymology, and a proposed production method for anti-inflammatory metabolites from Pseudopterogorgia elisabethae, J. Ind. Microbiol. Biotechnol., 30:495–499, 2003.

Look, S.A., Fenical, W., Jacobs, R.S., and Clardy, J., The pseudopterosins: Anti-inflammatory and analgesic natural products from the sea whip Pseudopterogorgia elisabethae, Proc. Natl. Acad. Sci. U.S.A., 83:6238–6340, 1986.

Mayer, A.M., Jacobson, P.B., Fenical, W., Jacobs, R.S., and Glaser, K.B., Pharmacological characterization of the pseudopterosins: Novel anti-inflammatory natural products isolated from the Caribbean soft coral, Pseudopterogorgia elisabethae, Life Sci., 62:PL401–PL407, 1998.

Psyllium

Psyllium is the mucilage obtained from the seed coat (husk or hull) of the plant genus Plantago. It has a long history of medicinal use because of its cholesterol-lowering, laxative, gastro-hypoacidity, and possibly weight-control properties (Anderson et al., 1990; Arjmandi et al., 1992; Hara et al., 1996; Park et al., 1997). A meta-analysis of 12 studies involving 404 adults with mild to moderate hypercholesterolemia by Olson et al. (1997) concluded that psyllium reduced total and LDL cholesterol by 5 percent and 9 percent, respectively. A study on 125 patients with type 2 diabetes by Rodriguez-Moran et al. (1998) found that treatment with 5 grams of psyllium t.i.d. over six weeks significantly reduced (p<0.05) fasting plasma glucose (Figure P.83), as well as total plasma cholesterol, LDL cholesterol, and triglycerides, while significantly increasing (p<0.01) HDL cholesterol.

Fang (2000) showed that psyllium improved the serum-lipid profiles in Sprague-Dawley rats by reversing the hypercholesterolemic effects of trans fatty acids. Recently, Marlett and Fischer (2003) reported that a gel-forming component in psyllium seeds, which was not fermented, was responsible for its laxative and cholesterol-lowering properties. The active fraction was a highly branched arabinoxylan consisting of a xylose backbone and arabinose-and xylose-containing side chains.

FIGURE P.83 Mean plasma-glucose levels. In the period of diet counseling (weeks 0–6), there were mild but not significant variations on glucose levels for both groups. The treatment beginning at week 6, and during all this period (to week 12), the patients on psyllium group (■) showed a greater and statistically significant reduction in plasma-glucose levels compared to the placebo group (●). Asterisk indicates a significant difference at p<0.01. (From Rodriguez-Moran et al., J. Diab. Comp., 12:273–278, 1998. With permission.)

Psyllium was shown to improve glucose homeostasis and the lipid and lipoprotein profiles in obese children and adolescents with abnormalities in carbohydrate and lipid metabolism (Moreno et al., 2003). Beneficial, therapeutic effects reported for psyllium include the metabolic control of type 2 diabetes, as well as lowering the risk of coronary heart disease (Sierra et al., 2002).

The synergistic effect of wheat bran and psyllium was shown by Albaster et al. (1993) to inhibit the early phases of carcinogenesis. Cohen et al. (1996) also reported the effects of wheat bran and psyllium diets in reducing N-methylnitrosourea-induced mammary tumorigenesis in F344 rats. The antitumor activity of psyllium was recently demonstrated by Nakamura et al. (2004), who showed it restored normal gap junctional intercellular communication (GJIC) and anchorage-independent growth (AIG) by reversing two tumor-cell phenotypes induced by the Ha-ras oncogene.

While no adverse effects have been associated with psyllium intake, nevertheless some individuals may be allergic to it (James et al., 1991). In addition, Luccia and Kunkel (2002) showed that an increase in soluble fiber from sources such as psyllium reduced calcium bioavailability in weanling Wistar rats, as well as had negative effects on bone composition. The increased consumption of psyllium, however, has since led to its recognition as an emerging food allergen (Khalili et al., 2003)

References

Alabaster, O., Tang, Z.C., Frost, A., and Shivapurkar, N., Potential synergism between wheat bran and psyllium: Enhanced inhibition of colon cancer, Cancer Lett., 75:53–58, 1993.

Anderson, J., Deakins, D.A., Floore, T.L., Smith, B.M., and Whitis, S.E., Dietary fiber and coronary heart disease, Crit. Rev. Food Sci. Nutr., 29:95–146, 1990.

Arjmandi, B.H., Craig, J., Nathani, S., and Reeves, R.D., Soluble dietary fiber and cholesterol influence in vivo hepatic intestinal cholesterol biosynthesis in rats, J. Nutr., 122:1559–1565, 1992.

Cohen, L.A., Zhao, Z., Zang, E.A., Wynn, T.T., Simi, B., and Rivenson, A., Wheat bran and psyllium diets: Effects on N-methylnitrosourea-induced mammary tumorigenesis in F344 rats, J. Natl. Cancer Inst., 88: 899–907, 1996.

Fang, C., Dietary psyllium reverses hypercholesterolemic effect of trans fatty acids in rats, Nutr. Res., 20:695–705, 2000.

Hara, H., Suzuki, K., Koyabashi, S., and Kasai, T., Fermentable property of dietary fiber may not determine cecal and colonic mucosal growth in fiber-fed rats, J. Nutr. Biochem., 7:549–554, 1996.

James, J.M., Cooke, S.K., Barnett, A., and Sampson, H.A., Anaphylactic reactions to psyllium-containing cereal, J. Allergy Clin. Immunol., 88:402–408, 1991.

Khalili, B., Bardana, E.J., Jr., and Yunginger, J.W., Psyllium-associated anaphylaxis and death: A case report and review of the literature, Ann. Allergy Asthma Immunol., 91:579–584, 2003.

Luccia, B.D.H. and Kunkel, M.E., Psyllium reduces calcium bioavailability and induces negative changes in bone consumption in weanling Wistar rats, Nutr. Res., 22:1027–1040, 2002.

Marlett, J.A. and Fischer, M.H., The active fraction of psyllium seed husk, Proc. Nutr. Soc., 62:207–209, 2003.

Moreno, L.A., Tresaco, B., Bueno, G., Fleta, J., Rodriguez, G., Garagorri, J.M., and Bueno, M., Psyllium fibre and the metabolic control of obese children and adolescents, J. Physiol. Biochem., 59:235–242, 2003.

Nakamura, Y., Trosko, J.E., Chang, C.-C., and Upham, B.L., Psyllium extracts decreased neoplastic phenotypes induced by the Ha-Ras oncongene transfected into a rat liver oval cell line, Cancer Lett., 203:13–24, 2004.

Olson, B.H., Anderson, S.M., Becker, M.P., Anderson, J.W., Hunninghake, D.B., Jenkins, D.J.A., Larosa, J.C., Rippe, J.M., Roberts, D.C.K., Stoy, D.B., Summerbell, C.D., Truswell, A.S., Wolever, T.M.S., Morris, D.H., and Fulgoni, V.L., Psylliumenriched cereals lowers blood total cholesterol and LDL cholesterol, but not HDL cholesterol, in hypercholesterolemic adults: Results EF a meta-analysis, J. Nutr., 127:1973–1980, 1997.

Park, H., Seib, P.A., and Chung, O.K., Fortifying bread with a mixture of wheat fiber and psyllium husk fiber plus three antioxidants, Cereal Chem., 74: 207–211, 1997.

Rodriguez-Moran, M., Guerrero-Romero, F., and Lazcano-Burciaga, G., Lipid- and glucoselowering efficacy of Plantago psyllium in type II diabetes, J. Diab. Comp., 12:273–278, 1998.

Sierra, M., Garcia, J.J., Fernandez, N., Diez, M.J., and Calle, A.P., Therapeutic effects of psyllium in type 2 diabetic patients, Eur. J. Clin. Nutr., 56:830–842, 2002.

Pulses

see also Beans, Lentils, and Soybeans Pulses are the health-promoting, edible seeds of leguminous plants grown for food and include peas, beans, and lentils (Messina et al., 1999). The nonnutrient, bioactive agents in pulses were reviewed by Champ (2002). While many were considered antinutritional factors, subsequent research suggests many of these compounds may play a role in the prevention of chronic diseases. A list of these compounds can be found in Table P.58.

Anderson and Major (2002) reviewed both the epidemiological and clinical data, which supported the hypocholesterolemic effect of soybean and pulses. In addition, they performed a meta-analysis of 11 clinical trials that showed pulses decreased cholesterol and LDL cholesterol while increasing HDL cholesterol. These effects were attributed to the presence of soluble dietary fiber, protein, oligosaccharides, isoflavones, phospholipids, fatty acids, and saponins. Additional benefits included reduction in blood pressure, glycemia, and the risk for obesity.

TABLE P.58
Major Nonnutrient Bioactive Pulse Compounds

References

Anderson, J.W. and Major, A.W., Pulses and lipaemia, short- and long-term effect: Potential prevention of cardiovascular disease, Br. J. Nutr., 88(Suppl. 3):S263–S271, 2002.

Champ, M.M.-J., Non-nutrient bioactive substances of pulses, Br. J. Nutr., 88(Suppl. 3):S307– S319, 2002.

Messina, M.J., Legumes and soybeans: An overview of their nutritional profiles and health effects, Am. J. Clin. Nutr., 70:439S-450S, 1999.

Purple corn color

Purple corn color (PCC) is a natural anthocyanin pigment that was found by Hagiwara and coworkers (2001) to have anticancer properties. When fed at a dietary level of 5 percent to male F344/DuCrj rats, pretreated with 1,2-dimethylhydrazine (DMH) to develop colorectal carcinogenesis, it suppressed lesions, as well as decreased the induction of aberrant crypts by the presence of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet.

References

Hagiwara, A., Miyashita, K., Nakanishi, T., Sano, M., Tamano, S., Kadota, T., Koda, T., Nakamura, M., Imaida, K., Ito, N., and Shirai, T., Pronounced inhibition by a natural anthocyanin, purple corn color, of 2-amino-1 -methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine, Cancer Lett., 171:17–25, 2001.

Pycnogenol

Pycnogenol is a mixture of oligomeric and monomeric procyandins isolated from the bark extract of French maritime pine (Pinus pinaster) (Masquelier, 1997). Composed of water-soluble procyanidins, catechin, taxofolin, and phenolcarbonic acid, it is used as a dietary supplement. Hosseini et al. (2001) showed Pycnogenol^® (200 mg/day) lowered diastolic blood pressure, but not statistically, in mildly hypertensive patients. However, serumthromboxane levels were reduced significantly during treatment.

Using a rat pheochromocytoma (PC 12) cell line, Peng et al. (2002) found Pycnogenol^® protected neurons from amyloid-β peptide-induced apoptosis, one of the pathological features associated with Alzheimer’s disease. Pycnogenol decreased the percentage of apoptotic cells and inhibited caspase-3 activation, DNA fragmentation, and poly(ADP-ribase) polynerase (PARP) cleavage. The possible involvement of oxidative stress was evident by Pycnogenol^®’s suppression of amyloid-β peptide’s generation of reactive-oxygen species (ROS), as evident in the presence of vitamin E. Thus, the antioxidant properties of Pycnogenol^® appeared partly responsible for reducing these cells from amyloid-β peptide’s neurotoxicity. Huang et al. (2005) recently reported Pycnogenol^® induced differentiation and apoptosis in human promyeloid leukemia HL-60 cells, suggesting it could act as a potent cancer chemopreventive or chemotherapeutic agent.

The role of ROS in inflammatory processes, such as rheumatic diseases, led to a recent study by Grimm et al. (2004) on matrix-degrading enzymes, matrix metalloproteinases (MMPs). MMPs are a family of zinc-dependent proteolytic enzymes activated by ROS that contribute to the inflammatory network (Visse and Nagase, 2003; Rajagopalan et al., 1996). Two major metabolites of the standardized pine-bark extract Pycnogenol^®, M1 and M2, were identified by Grosse-Duweler and Rohdewald (2000), with strong reducing power (Scheme P.49). Grimm et al. (2004) showed M1 and M2 strongly inhibited matrix metalloproteinase MMP-1, as shown in Figure P.84. Similar inhibitory effects were also observed on MMP-2 and MMP-9. M1 proved a more effective scavenger of superoxide than (+)-catechin, ascorbic acid, and trolox, while M2 had no scavenging activity. These results point to the potential prophylaxis and therapeutic uses of Pycnogenol^® in disorders resulting from an imbalance or excess of metalloproteinase activity.

Recent research by Liu et al. (2004a) suggested that supplementation of mildly hypertensive patients with Pycnogenol^® significantly reduced the dosage of the antihypertensive drug, nidipine. A double-blind, placebo-controlled, randomized, multicenter study by Liu et al. (2004b) on 77 diabetes type 2 patients also showed multiple benefits were derived from supplementation with 100 mg Pycnogenol^® over 12 weeks, including significantly lowering of plasma-glucose levels. Other benefits included inhibiting endothelin-1 production, expression of adhesion molecules, and platelet aggregation.

SCHEME P.49 The two main metabolites of Pycnogenol^® identified in human urine. (From Grosse-Duweler and Rohdewald, Pharmazie, 55:364–368, 2000. With permission.)

FIGURE P.84 Mean concentrations of Pycnogenol^®, M1, and M2 that produced 50 percent inhibition of MMP-1 activity toward degradation of collagen or gelatin, respectively. Each column represents the mean and SD of six independent experiments. Statistically significant differences between compounds are shown only for metabolite M1 (ANOVA with subsequent Tukey test). (From Grimm et al., Free Rad. Biol. Med., 36:811– 822, 2004. With permission.)

Durackova et al. (2003) found Pycnogenol^® was beneficial in the treatment of erectile dysfunction, as well as improving the atherogenic factor of lipoproteins and antioxidant status of plasma. Mantle et al. (2005) recently noted pycnogenol was part of a nutritional supplement that included calcium, carnitine, coenzyme Q₁₀, glucosamine, magnesium, methyl sulfonyl methane, silica, vitamin C, and vitamin K, which proved effective in treating Ehlers-Dantos syndrome, a rare, inherited disorder of the connective tissue.

References

Durackova, Z., Trebaticky, B., Novotny, V., Zitnanova, I., and Breza, J., Lipid metabolism and erectile function improvement by Pycnogenol^® extract from the bark of Pinus pinaster in patients suffering from erectile dysfunction—a pilot study, Nutr. Res., 23:1189–1198, 2003.

Grimm, T., Schafer, A., and Hogger, P., Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (Pycnogenol), Free Rad. Biol. Med., 36:811–822, 2004.

Grosse-Duweler, K.G. and Rohdewald, P., Urinary metabolites of French maritime pine bark extract in humans, Pharmazie, 55:364–368, 2000.

Hosseini, S., Lee, J., Sepulveda, R.T., Rohdewald, P., and Watson, R.R., A randomized, doubleblind, placebo-controlled, prospective, 16 week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients, Nutr. Res., 21:1251– 1260, 2001.

Huang, W.W., Yang, J.S., Lin, C.F., Ho, W.J., and Lee, M.R., Pycnogenol induces differentiation and apoptosis in human promyeloid leukemia HL-60 cells, Leukemia Res., 29:685–692, 2005.

Liu, X., Wei, J., Tan, F., Zhou, S., Wurthwein, G., and Rohdewald, P., Pycnogenol®, French maritime pine bark extract, improves endothelial function of hypertensive patients, Life Sci., 74:855–862, 2004a.

Liu, X., Wei, J., Tan, F., Zhou, S., Wurthwein, G., and Rohdewald, P., Antidiabetic effect of Pycnogenol^® French maritime pine bark extract in patients with diabetes type II, Life Sci., 75:2505–2513, 2004b.

Mantle, D., Wilkins, R.M., and Preedy, V., A novel therapeutic strategy for Ehlers-Danlos syndrome based on nutritional supplements, Med. Hypotheses, 64:279–283, 2005.

Masquelier, J., Plant extract with a proanthcyanidins content as therapeutic agent having radical scavenging effect and use thereof, U.S. patent 4,698,360, 1987.

Peng, Q.L., Buz’Zard, A.R., and Lau, B.H.S., Pycnogenol^® protects neurons from amyloid-β peptide-induced apoptosis, Mol. Brain Res., 104:55–65, 2002.

Rajagopalan, S., Meng, X.P., Ramasamy, S., Harrison, D.G., and Galis, Z.S., Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro: Implications for atherosclerotic plaque stability, J. Clin. Invest., 98:2572–2579, 1996.

Visse, R. and Nagase, H., Matrix metalloproteinases and tissue inhibitors of metaloproteinases: Structure, function, and biochemistry, Circ. Res., 92:827–839, 2003.