F
Farnesol
Farnesol, a nonsteroid isoprenoid intermediate formed from mevalonate, is found in orange-peel oil and lemon-grass oil. In mammalian cells, farnesol is metabolized to farnesal, farnesoic acid, and prenyldicarboxylic acids (Bostedor et al., 1997). Isoprenoids, such as farnesol, are involved in cell-signaling transduction, as its phosphorylated form, farnesyl pyrophosphate, is needed for protein prenylation (Gelb, 1997). Terpenoids, such as farnesol, with hydroxyl groups appear more active than terpene hydrocarbons by inhibiting MIA ZpaCa2 pancreatic-tumor cells (Burke et al., 1997). Farnesol was reported to inhibit the proliferation of some cell lines and induce apoptosis in a number of tumor-derived cell lines (Burke et al., 1997; Yasugi et al., 1994). Rioja et al. (2000) showed farnesol preferentially inhibited proliferation and induced apoptosis of leukemic cells without affecting normal, nontransformed cell lines.
Farnesol. (Adapted from Rao et al., Cancer Det. Prev., 26:419–425, 2002.)
Raner et al. (2002) observed that only farnesol, and not related isoprenoids, geranylgeraniol, geranylgeranyl pyroposphate (GGPP), and farnesyl pyrophosphate (FPP), inhibited certain rabbit-liver microsomal cytochrome P450 enzymes (Table F.26). Since cytochrome P450 plays a prominent role in the metabolism of pharmaceuticals and activation of potential carcinogens, its inhibition has important health benefits. Studies on AOM-induced colon carcinogenesis in rats by Rao et al. (2002) noted the chemopreventive properties of farnesol as it inhibited the formation of preneoplastic lesions in rats fed a diet containing 1.5 percent farnesol. Farnesol significantly inhibited ACF formation by 34 percent, while reducing multiplicity by 44 percent.
References
Bostedor, R.G., Karkas, J.D., Arisen, B.H., Bansai, V.S., Vaidya, S., Gemershausen, J.I., Kurtz, M.M., and Bergstrom, J.D., Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol, J. Biol. Chem., 272:9197–9203, 1997.
Burke, Y.D., Stark, M.J., Roach, S.L., Sen, S.E., and Crowell, P.L., Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol, Lipids, 32:151–156, 1997.
Gelb, M.H., Protein prenylation, et cetera: Signal transduction in two dimensions, Science, 275:1750–1751, 1997.
Raner, G.M., Muir, A.Q., Lowry, C.W., and Davis, B.A., Farnesol as an inhibitor and substrate for rabbit liver microsomal P450 enzymes, Biochem. Biophys. Res. Commun., 293:1–6, 2002.
Rao, C.V., Newmark, H.L., and Reddy, B.S., Chemopreventive effect of farnesol and lanosterol on colon carcinogenesis, Cancer Det. Prev., 26:419–425, 2002.
Rioja, A., Pizzey, A.R., Marson, C.M., and Thomas, N.S.B., Preferential induction of apoptosis of leukemic cells by farnesol, FEBS Lett., 467:291–295, 2000.
Yasugi, E., Yokoyama, Y., Seyama, Y., Kano, K., Hayashi, Y., and Oshima, M., Dolichyl phosphate, a potent inducer of apoptosis in rat glioma C6 cells, Biochem. Biophys. Res. Commun., 216:848–853, 1995.
Fennel
Fennel (Foeniculum vulgare Mill.) is an aromatic herb grown in Europe and Asia. The essential oil from the seeds of fennel has been used in foods, cosmetics, and pharmaceuticals. The major constituent of fennel oil is (E)-anethole (80 percent), followed by methyl chavicol (10 percent) and fenchone (7.5 percent) (Brand, 1993). Minor constituents include γ-pinene, limonene, β-pinene, α-myrcene, and para-cymene (Brand, 1993; Toth, 1967; Trenkle, 1972). The essential oil of Foeniculum vulgare was found by Ozbeck et al. (2003) to exert a potent hepatoprotective effect against carbon tetrachloride (CCl4)-induced liver damage in rats.
Arethole chavical. (Adapted from Gross et al., Plant Sci., 163:1047– 1053, 2002.)
Fennel seeds have been reported to promote menstruation, alleviate female climacteric, as well as increase libido (Albert-Puelo, 1980). Because of its antispasmodic effects, it has been used to treat some respiratory disorders (Reynolds, 1982). In folk medicine, fennel has been used to treat a number of gynecological complaints, such as dysmenorrhea, a condition of severe pain during menstruation. One of the major reasons for primary dysmenorrhea is increased ectopic uterine motility. Ostad et al. (2001) showed fennel essential oil significantly reduced the intensity of oxytocin- and PGE2-induced uterine contractions obtained from virgin Wistar rats. Subsequent work by Namavar Jahromi et al. (2003) compared the effectiveness of sweet fennel (Foeniculum vulgare var. duice) and mefenamic acid in the treatment of primary dysmenorrhea in 70 women 15–24 years old, suffering from this problem. The results in Table F.27 show mefanamic acid was more effective in reducing pain intensity on the second and third days of menstruation, but there were no significant differences on any of the other days. This study corroborates earlier studies confirming the effectiveness of fennel extract in treating primary dysmenorrhea.
References
Albert-Puleo, M., Fennel and anise as estrogenic agent, J. Ethonopharmacol., 2:337–344, 1980.
Brand, N., 1993. Hagers handbuch der pharmazeutischen praxis, in Hansel, R., Keller, K., Rimpier, H., and Schneider, G., Eds., Springer-Verlag, Berlin/Heidelberg, 5, 1993, pp. 156–181.
Gross, M., Friedman, J., Dudai, N., Larkov, O., Cohen, Y., Bar, E., Ravid, U., Putievsky, E., and Lewinsohn, E., Biosynthesis of estragole and t-anethole in bitter fennel (Foeniculum vulgare Mill. Var. vulgare) chemotypes, Changes in SAM: phenylpropene O-methyltransferase activities during development, Plant Sci., 163:1047–1053, 2002.
Namavar Jahromi, B.N., Tartifizadeh, A., and Khabnadideh, S., Comparison of fennel and mefenamic acid for the treatment of primary dysmenorrhea, Inter. J. Gynecol. Obstr., 80:153– 157, 2003.
Ozbek, H., Ugras, S., Dulger, H., Bayram, I., Tuncer, I., Ozturk, G., and Ozturk, A., Hepatoprotective effect of Foeniculum vulgare essential oil, Fitoterapia, 74:317–319, 2003.
Reynolds, E.F.J.F., Essential oils and aromatic carminatives, The Extra Pharmacopeia 28th edition. Royal Pharmaceutical Soc., Martindale, Lond. 1982, p. 670–676.
Toth, L., Studies on the etheric oil of Foeniculum vulgare, II. Changes of different fennel oils before and after harvest, Planta Med., 15:371, 1967.
Trenkle, K., Recent studies on fennel (Foeniculum vulgare M.), 2. The volatile oil of the fruit, herbs and roots of fruit-bearing plants, Pharmazie, 27:319–324, 1972.
Fenugreek
Fenugreek (Trigonella foenum graecum) seeds, widely used as a condiment, have also proved beneficial in India for the treatment of gastric disorders (Puri, 1968). They were shown to be beneficial in treating diabetics and hypercholesterolemic patients (Sharma et al., 1996). Pandian and coworkers (2002) reported that several fenugreek fractions were effective in treating an HCl-ethanol-induced gastric ulcer in rats compared to one of the commonly prescribed drugs, omeprazole. Fenugreek seeds were extracted with water and centrifuged with the supernatant used as the aqueous extract. A gel fraction was also pre pared, following the procedure of Madar and Shomer (1990), which represented the polysaccharides of the seed coat. The severity of the ulcers was reduced markedly, following pretreatment of the rats with the fenugreek fractions prior to HCl-ethanol treatment. Maximum inhibition was observed with doses of 3 mL of the aqueous fractions and 700 mg of the gel fraction, with the results summarized in Table F.28. The fenugreek fraction proved to be as effective as omeprazole against the ulcerogenic effects of ethanol. Lipid peroxidation, as measured by TBARS, was found to be significantly lower in the pretreated rats compared to ethanol-treated rats, suggesting antioxidant activity in the fenugreek extracts, due possibly to the presence of flavonoids.
Al-Habouri and Raman (1998) reviewed the literature related to antidiabetic and hypocholesterolemic effects of fenugreek. While the antidiabetic effects were attributed to the gum fiber, the hypolipidemic effects were due to the saponins and sapogenins confined fiber. The lack of toxicity associated with fenugreek makes it excellent for management of diabetes and hypercholesterolemia. Recent work by BinHafeez et al. (2003) showed fenugreek also had appreciable immunostimulatory activity.
Concern was raised regarding the potential of fenugreek to react with medications, such as warfarin (Lambert and Cormier, 2001; Heck et al., 2000). In addition, fenugreek may also potentiate antihypertensive and antidiabetic medication, as well as increase the risk of bleeding in women taking nonsteroidal antiinflammatories, such as aspirin (Abebe, 2002).
Tiran (2003) cautioned women with such preexisting conditions as gastrointestinal upset, diabetes, hypertensive disease, and cardiac disease or who are breast-feeding against using fenugreek.
References
Abebe, W., Herbal medication: Potential for adverse interactions with analgesic drugs, J. Clin. Pharm. Ther., 27:391–401, 2002.
Al-Habori, M. and Raman, A., Antidiabetic and hypocholesterolemic effects of fenugreek, Phytother. Res., 12:233–242, 1998.
Bin-Hafeez, B., Haque, R., Parvez, S., Pandey, S., Sayeed, I., and Raisuddin, S., Immunomodulatory effects of fenugreek (Trigonella foenum graecum L.) extract in mice, Inter. Immunopharmacol., 3:257–265, 2003.
Heck, A.M., De Witt, B.A., and Lukes, A.L., Potential interactions between alternative therapies and warfarin, Am. J. Health System Pharm., 17:1221–1227, 2000.
Lambert, J.P. and Cormier, A., Potential interaction between warfarin and boldo-fenugreek, Pharmacotherapy, 21:509–512, 2001.
Madar, Z. and Shomer, I., Polysaccharide composition of a gel fraction derived from fenugreek and its effect on starch digestion and bile acid absorption in rats, J. Agric. Food Chem., 38:1535– 1539, 1990.
Pandian, R., Anuradha, C.V., and Viswanathan, P., Gastroprotective effect of fenugreek seeds (Trigonella foenum graecum) on experimental gastric ulcer in rats, J. Ethnopharmacol., 81:393– 397, 2002.
Puri, D., Therapeutic potentials of fenugreek, Indian J. Physiol. Pharmacol., 42:423–424, 1998.
Sharma, R.D., Sarkar, A., Hazra, D.K., and Misra, B., Hypolipidaemic effect of fenugreek seeds: A chronic study in non-insulin dependent diabetic patients, Phytotherapy Res., 10:332–334, 1996.
Tiran, D., The use of fenugreek for breast feeding women, Compl. Ther in Nurs. Midwif., 9:155– 156, 2003.
Ferulic acid
Ferulic acid, found widely in fruits and vegetables, has strong antioxidant properties against peroxynitrite (Pannala et al., 1998) and oxidized low-density lipoprotein in vitro (Schroeder et al., 2000). Kanski and coworkers (2002) showed ferulic greatly reduced free-radical damage in neuronal-cell systems without causing cell death by protecting them against oxidative stress from hydroxyl and peroxyl radicals. This study pointed to the importance of natural antioxidants, such as ferulic acid, as a therapeutic agent against neurodegenerative disorders, such as Alzheimer’s disease. A novel chemical derivative of ferulic acid (FA 15) made by Murakami et al. (2000) to suppress phorbol ester-induced Epstein-Barr virus activation and superoxide anion generation in vitro. Murakami and coworkers (2002) later showed that, unlike ferulic acid, FA 15 significantly attenuated phorbol ester-triggered hydrogen-peroxide production, edema formation, and papilloma development in ICR mouse skin. The ferulic-acid derivative, FA 15, appeared to be a novel chemopreventive agent.
Ferulic acid. (Adapted from Pannala et al., Free Rad. Biol. Med., 24:594–606, 1998.)
TABLE F.29
Incidence and Multiplicity of Intestinal Tumors in Each Group1
Ferulic acid was also a potent inhibitor of mutagenesis and carcinogenesis induced by polycyclic aromatic hydrocarbon. For example, ferulic acid prevented 4-nitroquinoline 1-oxide (4-QO)-induced tongue carcinogenesis in rats (Tanaka et al., 1993) and depressed TPA-induced skin tumorigenesis and pulmonary cancers in mice (Asanoma et al., 1994; Lesca, 1983). Kawabata et al. (2000) reported dietary ferulic acid significantly reduced the total number of aberrant crypt foci (ACF) in the colon of azoxymethane-treated (AOM) male rats. The incidence and multiplicity of intestinal neoplasms were also significantly reduced, as shown in Table F.29. The values obtained in the intestine, in the presence of ferulic acid, tended to be lower compared to treatment with AOM alone. The multiplicity of tumors in the entire intestine was significantly reduced in groups 2 and 3, in the large intestine in group, compared to group 1. The blocking effect of ferulic acid on AOM-induced colon carcinogenesis appeared to be related to its significant elevation of phase II detoxifying enzymes, glutathione S-transferase in the liver, and quinone reductase in the liver and colinic mucosa.
Rouau and coworkers (2003) recently detected a trimer of ferulic acid in alkali extracts of maize bran. Using 1D and 2D NMR, the structure of the trimer was identified as 4-O- 8′,5′-dehydrotriferulic acid.
References
Asanoma, M., Takahashi, K., Miyabe, M., Yamanoto, K., Yoshimi, N., Mori, H., and Kawazoe, Y., Inhibitory effect of topical application of polymerized ferulic acid, a synthetic lignin, on tumor promotion in mouse skin two-stage tumorigenesis, Carcinogenesis, 15:2069–2071, 1994.
Kawabata, K., Yamanoto, T., Hara, A., Shimizu, M., Yamada, Y., Matsunaga, K., Tanaka, T., and Mori, H., Modifying effects of ferulic acid on azoxymethane-induced colon carcinogenesis, Cancer Lett., 157:15–21, 2000.
Kanski, J., Aksenova, M., Stoyanova, A., and Butterfield, D.A., Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: Structure-activity studies, J. Nutr. Biochem., 13:273–281, 2002.
Lesca, P., Protective effects of ellagic acid and other plant phenols on benzo[s]pyrene-induced neoplasia in mice, Carcinogenesis, 4:1651–1653, 1983.
Murakami, A., Kadota, M., Takahashi, D., Taniguchi, H., Nomura, E., Hosoda, A., Tsuno, T., Maruta, Y., Ohogashi, H., and Koshimizu, K., Suppressive effects of novel ferulic acid derivatives on cellular responses induced by phorbol ester by combined lipolysaccharide and interferon-gamma, Cancer Lett., 157:77–85, 2000.
Murakami, A., Nakamura, Y., Koshimizu, K., Takahashi, D., Matsumoto, K., Hagihara, K., Taniguchi, H., Nomura, E., Hosoda, A., Tsuno, T., Maruta, Y., Kim, H.W., Kawabata, K., and Ohigashi, H., FA15, a hydrophobic derivative of ferulic acid, suppresses inflammatory responses and skin tumor promotion: Comparison with ferulic acid, Cancer Lett., 180:121–129, 2002.
Pannala, R., Razaq, B., Halliwell, S., Singh, C.A., and Rice-Evans, C.A., Inhibition of peroxynitrite dependent tyrosine nitration by hydroxycinnamates: Nitration or electron donation? Free Rad. Biol. Med., 24:594–606, 1998.
Rouau, X., Cheynier, V., Surget, A., Gloux, D., Barron, C., Meudec, E., Louis-Montero, J., and Criton, M., A dehydrotrimer of ferulic acid from maize bran, Phytochemistry, 63:899–903, 2003.
Schroeder, H., Williams, R.J., Martin, R., Iversen, L., and Rice-Evans, C.A., Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoproteins, Free Rad. Biol. Med., 29:1222–1233, 2000.
Tanaka, T., Kojina, T., Kawamori, T., Wang, A., Suzui, M., Okamoto, K., and Mori, H., Inhibition of 4-nitroquinoline-1-oxide induced rat tongue carcinogenesis by the naturally occurring plant phenolics caffeic, ellagic, chlorogenic and ferulic acids, Carcinogenesis, 14:1321–1325, 1993.
Feverfew
Feverfew (Tanacetum parthenium L.), an aromatic herb, has been used as folk medicine for the treatment of migraine and arthritis (Berry, 1984; Johnson, 1984). Biological activity reported in the crude extracts from feverfew leaves may explain its therapeutic and anti-inflammatory properties. Such activity includes inhibition of platelet aggregation (Groenewegen and Heptinstall, 1990) and release of histamine from mast cells (Hayes and Foreman, 1987), as well as antinociceptive and anti-inflammatory activities in mice and rats (Jain and Kulkarni, 1999). Several sesquiterpene ά-methylene butyrolactones in feverfew extracts, exhibiting these properties, were identified as parthenolide and canin. Piela-Smith and Liu (2001) attributed the anti-inflammatory properties of feverfew extracts and parthenolid to their ability to inhibit the expression of proinflammatory cellular-adhesion molecules in cultured synovial fibroblasts obtained from rheumatoid-arthritis patients. Figure F.39 shows feverfew extract and parthenolide both inhibited the expression of an inflammation-related adhesion molecule, VCAM-1, induced by TNF. Kwok et al. (2001) examined the molecular basis for parthenolide’s ability to inhibit the proinflammatory signaling pathway. They found it bound and inhibited the IκB kinase, a multisubunit complex responsible for cytokinemediated stimulation of genes involved in the inflammation process. Smolinski and Pestka (2003) confirmed the anti-inflammatory properties of three herbal constituents, including parthenolide on lipopolysaccharide-induced (LPS), proinflammatory cytokine production. They found that the data from cell culture could not accurately predict the effect in animals so that animal models were still needed for confirmation. Fiebich and coworkers (2002) were the first to report parthenolide-inhibited activation of p42/44 mitogen-activated protein kinase (MAPK), which reduced the production of inducible nitric-oxide synthase (iNOS) synthesis and nitric-oxide release. Since nitric oxide is implicated in the etiology of central-nervous system (CNS) diseases, such as multiple sclerosis, their results suggested parthenolide may have potential for treating CNS diseases where NO is part of the pathophysiology.
Parthenolide. (From Miglietta et al., Chemico-Biol. Interactions, 149:165–173, 2004. With permission.)
FIGURE F.39 Feverfew and parthenolide inhibition of synovial VCAM-1. Synovial FB was pretreated with feverfew extract (Ex) (1:80) or parthenolide (P) (2.0 and 1.5 μg/mL) for 4 h prior to treatment with TNF (500 μ/mL). (From Piela-Smith and Liu, Cell Immunol., 209:89–96, 2001. With permission.)
Pittler and coworkers (2000) systematically reviewed evidence for feverfew’s efficacy to treat migraine. They concluded that the prevention of migraine by feverfew was still to be established. Nelson et al. (2002) showed that while the quantity of feverfew leaves in each capsule sold to consumers was similar, the parthenolide content per dosage form varied by as much as 150-fold and the percent parthenolide by 5.3-fold. The lack of standardization of feverfew products could explain the variability in efficacy.
References
Berry, M.I., Feverfew faces the future, Pharm. J., 232:611–614, 1984.
Fiebich, B.L., Lieb, K., Engels, S., and Heinrich, M., Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells, J. Neuroimmunol., 132:18–24, 2002.
Groenewegen, W.A. and Heptinstall, S., A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in vitro, J. Pharm. Pharmacol., 42: 553–557, 1990.
Hayes, N.A. and Foreman, J.C., The activity of compounds extracted from feverfew on histamine release from rat mast cells, J. Pharm. Pharmacol., 39:466–470, 1987.
Jain, N.K. and Kulkarni, S.K., Antinociceptive and anti-inflammatory effects of Tanacetum parthenium L. extract in mice and rats, J. Ethnopharmacol., 68: 251–259, 1999.
Johnson, E.S., Feverfew: A Traditional Herbal Remedy for Migraine and Arthritis, Sheldon Press, London, 1984.
Kwok, B.H.B., Koh, B., Ndubuisio, M.I., Elofsson, M., and Crews, C.M., The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IκB kinase, Chem. Biol., 8:759–766, 2001.
Miglietta, A., Bozzo, F., Gabriel, L., and Bocca, C., Microtubule-interfering activity of parthenolide, Chemico-Biol. Interactions, 149:165–173, 2004.
Nelson, M.H., Cobb, S.E., and Shelton, J., Variations in parthenolide content and daily dose of feverfew products, Am. J. Health Syst. Pharm., 15:1527–1531, 2002.
Piela-Smith, T.H. and Liu, X., Feverfew extracts and the sesquiterpene lactone parthenolide inhibit intercellular adhesion molecule-1 expression in human synovial fibroblasts, Cell Immunol., 209:89–96, 2001.
Pittler, M.H., Vogler, B.K., and Ernst, E., Feverfew for preventing migraine, Cochrane Database Syst. Rev., CD002286, 2000.
Smolinksi, AT. and Pestka, J.J., Modulation of lipopolysaccharide-induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb1 (ginseng) and paryhenolide (feverfew), Food Chem. Toxicol., 41:1381–1390, 2003.
Fish
There have been some reported studies of an inverse relationship between fish consumption and cardiovascular disease (Kromhout et al., 1985). Ecological studies suggest an inverse relationship between the incidence and mortality from cancer and fish consumption (Caygill et al., 1996; Kaizer et al., 1989). A recent panel report that reviewed epidemiological studies concluded that fish may protect against colon, rectal, and ovarian cancers (World Cancer Research Fund, American Institute for Cancer Research, 1997). Fernandez and coworkers (1999) examined the relation between the frequency of fish consumption and the risk of certain selected types of cancers in patients in northern Italy between 1983 and 1996. Their study suggested that even a small amount of fish reduced the risk particular of digestive-tract cancers.
References
Caygill, C.P.J., Charlett, A., and Hill, M.J., Fat, fish, fish oil and cancer, Br. J. Cancer, 74:159– 164, 1996.
Fernandez, E., Chatenoud, L., La Vecchia, C., Negri, E., and Franceschi, S., Fish consumption and cancer risk, Am. J. Clin. Nutr., 70:85–90, 1999.
Kaizer, L., Boyd, L., Kriukov, V., and Tritchler, D., Fish consumption and breast cancer risk: an ecological study, Nutr. Cancer, 1:61–68, 1989.
Kromhout, D., Bosschieter, E.B., and de Lezenne, C.C., The inverse relation between fish consumption and 20-year mortality from coronary heart disease, N. Engl. J. Med., 312:1205– 1209, 1985.
World Cancer Research Fund, American Institute for Cancer Research, Food, Nutrition and the Prevention of Cancer: A Global Perspective, American Institute for Cancer Research, Washington, D.C., pp. 452–459, 1997.
Fish oil
see also Docoahexaenoic and Eicosopentaenoic acids Fish oils are rich in polyunsaturated fatty acids (PUFAs), particularly ω-3 fatty acids, which are known to reduce cholesterol. Chen and Auborn (1999) showed docosahexaenoic acid (DHA) in fish oil selectively inhibited the growth of human papillo-marvirus (HPV) type 16 compared to eicosapentaenoic acid (EPA). These inhibitory effects were mediated via lipid peroxidation as α-tocopherol abrogated the effects of DHA. Liu et al. (2001) showed that a daily intake of a small amount of fish oil in bread fed to hyperlipidemic subjects significantly increased omega-3 fatty acids and HDL cholesterol levels, while decreasing triglycerides and malondialdehyde levels, reducing the risk of cardiovascular disease. A single-center, eight-month, randomized, double-blind, placebo-controlled study of 206 healthy nonsmoking subjects by Khan et al. (2003) showed the beneficial effects of fish oil on endothelial function. An increase of 6 percent EPA and 27 percent DHA in the diet, equivalent to eating oily fish two to three times per week, may significantly improve cardiovascular function and health.
In vitro studies with PUFAs from fish oil were found to enhance the efficacy of chemotherapeutic drugs against different cancer-cell types, such as MDA-MB 231 breast-cancer cells (Hardman et al., 1997), leukemic cells (De Salis and Meckling-Gill, 1995), and THKE tumorigenic human kidney epithelial cells (Maehle et al., 1995). The growth of human A549 lung-cancer cells, implanted subcutaneously on the backs of nude mice, was studied by Hardman and coworkers (2000a), who examined the change in the diet to 20 percent corn oil or 19 percent fish oil/1 percent corn oil on tumor growth. The growth of tumors was divided into two phases: phase I included the first 10 days on corn oil or fish diets plus four days for initiation of treatment with doxorubicin (DOX), commonly used in chemotherapy. Phase II commenced on the 14th day to allow sufficient time for DOX treatment to effect tumor size. No significant differences were observed in the rate of tumor growth in phase I, irrespective of the diets. During phase II, however, the tumors in animals consuming the fish-oil diet treated with iron and DOX were significantly regressed (Table F.30). In sharp contrast, the tumors in animals fed corn oil and treated with iron and DOX continued to grow. This study confirmed the potential benefit of fish oil as an adjuvant in the treatment of cancer. A combination of fish oil and butyrate-producing fiber pectin was shown by Hong and coworkers (2002) to upregulate apoptosis in colon cells exposed to the carcinogen azoxymethane. This effect was attributed to the oxidation of unsaturated mitochondrial lipids in fish, leading to an in increase in reactive-oxygen species.
TABLE F.30
Growth Rate of A549 Human Lung Tumors (Mean mm3 Per Day+SD of Slope)
A recent study by Pedersen and coworkers (2003) showed fish oil increased in vivo oxidation and in vitro susceptibility of LDL particles to oxidation in type 2 diabetic patients, characteristic of proatherogenic behavior. This contrasts with the beneficial effects that fish oil has on inflammation and heart disease, requiring more studies to establish its clinical significance.
References
Chen, D. and Auborn, K., Fish oil constituent docosahexaenoic acid selectively inhibits growth of human papillomavirus immortalized keratinocytes, Carcinogenesis, 20:249–254, 1999.
De Salis, H.M. and Meckling-Gill, K.A., EPA and DHA alter nucleoside drug and doxorubicin toxicity in L1210 cells but not in normal murine S1 macrophages, Cell Pharmacol., 2:69–74, 1995.
Hardman, W.E., Barnes, C.J., Knight, C.W., and Cameron, I.L., Effects of iron supplementation and ET-18-OCH3 on MDA-MB 231 breast carcinomas in nude mice consuming a fish oil diet, Br. J. Cancer, 76:347–354, 1997.
Hardman, W.E., Moyer, M.P., and Cameron, I.L., Dietary fish oil sensitizes A549 lung xenografts to doxorubicin chemotherapy, Cancer Lett., 151:145–151, 2000a.
Hardman, W.E., Moyer, M.P., and Cameron, I.L., Erratum to dietary fish oil sensitizes A549 lung xenografts to doxorubicin chemotherapy, Cancer Lett., 158:109, 2000b.
Hong, M.Y., Chapkin, R.S., Barhoumi, R., Burghardt, R.C., Turner, N.D., Henderson, C.E., Sanders, L.M., Fan, Y.-Y., Davidson, L.A., Murphy, M.E., Spinka, C.M., Carroll, R.J., and Lupton, J.R., Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive oxygen species and apoptosis in rat colonocytes, Carcinogenesis, 23: 1919–1926, 2002.
Khan, F., Elherik, K., Bolton-Smith, C., Barr, R., Hill, A., Murrie, I., and Belch, J.J.F., The effects of dietary fatty acid supplementation on endothelial function and vascular tone in healthy subjects, Cardiovasc. Res., 59:955–962, 2003.
Liu, M., Wallin, R., and Saldeen, T., Effect of bread containing stable fish oil on plasma phospholipid fatty acids, triglycerides, HDL-cholesterol, and malondialdehyde in subjects with hyperlipidemia, Nutr. Res., 21:1403–1410, 2001.
Maehle, L., Eilertsen, E., Mollerup, S., Schonberg, S., Krokan, H.E., and Haugen, A., Effects of n-3 fatty acids during neoplastic progression and comparison of in vitro and in vivo sensitivity of two human tumor cell lines, Br. J. Cancer, 71:691–696, 1995.
Pedersen, H., Petersen, M., Major-Pedersen, A., Jensen, T., Nielsen, N.S., Lauridsen, S.T., and Marckmann, P., Influence of fish oil supplementation on in vivo and in vitro oxidation resistance of lowdensity lipoprotein in type 2 diabetes, Eur. J. Clin. Nutr., 57:713–720, 2003.
Flavonoids
Flavonoids include a diverse group of more than 8000 polyphenolic compounds responsible for the antioxidant properties of fruits, vegetables, and herbs. The average daily intake of flavonoids in our diet was estimated to be around 1 g (Pierpoint, 1986). Flavonoids can be classified into eight groups, shown by their different basic skeleton structures, shown in Scheme F.22.
Examples of flavonoids are quercetin, myricetin, kempferol, and morin, characterized by a common ring structure, or flavone, but differing in the number and location of hydroxyl groups (Scheme F.23).
Zhu et al. (1999) found quercetin was most effective in protecting LDL from oxidation, followed by myricetin. Kampferol and morin exerted similar but much-less-protective effects, while ascorbic showed little or no effect (Figure F.40). Differences in efficacy among various flavonoids appeared to be related to the number and location of hydroxyl groups on the B ring and their stability in sodium-phosphate buffer. This was confirmed in a recent study by Peng and Kuo (2003), which also found antioxidant activity was much stronger in quercetin and myricetin because of their o-dihydroxyl or vicinal-trihydroxyl groups. Kampferol, with a single hydroxyl in the B ring, did not protect Caco-2 cells from lipid peroxidation. The ability of flavonoids to scavenge peroxynitrite, a cytotoxic intermediate formed from superoxide anion and nitric oxide, was also shown by Choi et al. (2002) to be dependent on the position of the hydroxyl group. Quercetin with an orthohydroxyl structure was the most potent scavenger, with an IC50 of 0.93 μM.
SCHEME F.22 Structures of basic flavonoid skeletons. (From Hodak, et al., Chem. Biol. Interact, 139:1–21, 2002. With permission.)
SCHEME F.23 Structures of kaemferol, morin, quercetin, and myricetin. (From Zhu et al., J. Nutr. Biochem., 11:14–21, 2000. With permission.)
FIGURE F.40 Inhibitory effect of four flavonoids on the production of TBARS in Cu2+-mediated oxidation of human low-density lipoprotein (LDL). Data expressed as means±SD of five samples. (Zhu et al., J. Nutr. Biochem., 11:14–21, 2000. With permission.)
The neuroinflammatory disease multiple sclerosis (MS) is characterized by demyelination. A recent study by Hendriks et al. (2003) showed flavonoids had therapeutic potential because of their ability to limit the demyelination process in the myelin of adult mice brain tissue. The most effective flavonoids were quercetin, luteolin, and fisetin, with hydroxyl groups at the B-3 and B-4 positions in combination with a C-2, 3 double bond.
Kobayashi and coworkers (2002) showed flavonoids were potent regulators of cyclin B and p21 for cell-cycle progression in human LNCaP prostate-cancer cells, and could play a preventative role in carcinogenesis.
In a review of flavonoids, Hodek et al. (2002) pointed out that while many of them exert beneficial effects, some may have mutagenic and prooxidant effects. Interaction of some flavonoids with cytochrome P450 (CYP) can result in enhanced activation of carcinogens or influence drug metabolism. In contrast, however, other flavonoids may have a beneficial effect by inhibiting activation of carcinogens by CYPs. Interaction of some flavonoids with prescribed drugs can lead to altered pharmacokinetics by either increasing their toxicity or reducing their therapeutic effects, depending on their structure (Tang and Stearns, 2001). For example, naringenin and bergamottin in grapefruit juice can lead to impaired hepatic metabolism of certain drugs (He et al., 1998; Bailey et al., 2000). The indiscriminate use of herbal products containing a wide range of flavonoids can similarly affect the efficacy and toxicity of drugs.
References
Bailey, D.G., Dresser, G.R., Kreeft, J.H., Munoz, C., Freeman, D.J., and Bend, J.R., Grapefruitfelodipine interaction: Effect of unprocessed fruit and probable active ingredients, Clin. Pharmacol. Ther., 68:468–477, 2000.
Choi, J.S., Chung, H.Y., Kang, S.S., Jung, M.J., Kim, J.W., No, J.K., and Jung, H.A., The structure-activity relationship of flavonoids as scavengers of peroxynitrite, Phytother. Res., 16:232–235, 2002.
He, K., Iyer, K.R., Hayes, R.N., Sinz, M.W., Woolf, T.F., and Hollenberg, P.F., Inactivation of cytochrome p450 3 A4 by bergamottin, a component of grapefruit juice, Chem. Res. Toxicol., 11:252–259, 1998.
Hendriks, J.J.A., de Vries, H.E., van der Pol, S.M.A., van den Berg, T.K., van Tol, E.A.F., and Dijkstra, C.D., Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study, Biochem. Pharmacol., 65:877–885, 2003.
Hodek, P., Trefil, P., and Stiborova, M., Flavonoids—potent and versatile biologically active compounds interacting with cytochromes P450, Chem. Biol. Interact., 139:1–21, 2002.
Kobayashi, T., Nakata, T., and Kuzumaki, T., Effect of flavonoids on cell cycle progression in prostate cancer cells, Cancer Lett., 176:17–23, 2002.
Peng, I.W. and Kuo, S.M., Flavonoid structure affects the inhibition of lipid peroxidation in Caco-2 intestinal cells at physiological concentrations, J. Nutr., 133:2184–2187, 2003.
Pierpoint, W.S., Flavonoids in the human diet, in Progress in Clinical and Biological Research, Vol. 213, Cody, V., Middleton, E., Jr., and Harborne, J.B., Eds., Alan R.Liss, New York, 1986, pp. 125–140.
Tang, W. and Stearns, R.A., Heterotropic cooperativity of cytochrome P450 3A4 and potential drugdrug interactions, Curr. Drug. Metab., 2:185–188, 2001.
Zhu, Q.Y., Huang, Y., and Chen, Z.-Y., Interaction between flavonoids and α-tocopherol in human low density lipoprotein, J. Nutr. Biochem., 11:14–21, 1999.
Flaxseed
Flaxseed is obtained from flax (Linum usitatissimum), a versatile, blue-flowered crop. The seed, flat and oval with a pointed tip, is rich in protein, fat, and dietary fiber. Flaxseeds are one of the richest sources of the omega-3 fatty acid α-linolenic acid (ALA) (Oomah and Mazza, 2000). In addition, flaxseeds are also rich in phenolic compounds, particularly lignans, and dimers with a 2,3-dibenzylbutane structure (Harris and Haggerty, 1993). The lignan precursor in flaxseed is secoisolariciresinol diglycoside, or SDG, which appears to have some important health benefits. Yan et al. (1998) showed that supplementation of flaxseed in the diet reduced metastasis, the spread of malignant cells, in experimental mice with melanoma cells. Further work by Li et al. (1999) showed that dietary supplementation with SDG significantly decreased the number of lung tumors (Table F.31). In the control group, 59 percent (16 out of 27) of the mice had >50 tumors compared to 30, 21, and 22 percent of mice fed diets containing 73, 147, and 293 μmol/kg SDG. A significant decrease in tumor cross-sectional area and volume were also observed with SDG-fed mice in a dosedependent manner. Dabrosin and coworkers (2002) found that the addition of 10 percent flaxseed in the diet of nude mice with human breast-cancer xenografts showed a reduction in tumor growth and metastasis.
Secoisolariciresinol diglycoside. (From Rickard et al, Cancer Lett., 161:47–55, 2000. With permission.)
TABLE F.31
Effect of Dietary Supplementation with SDG on Pulmonary Metastasis Cells in Mice
The presence of ALA in flaxseed appeared to protect against cardiovascular disease (Allman et al., 1995; Ferretti and Flanagan, 1996). Consumption of flaxseed either raw or defatted was shown to reduce total and LDL cholesterol in human subjects (Cunnane et al., 1993; Jenkins et al., 1999). Flaxseed oil was also found to be a potent inhibitor of proinflammatory mediators (Caughey et al., 1996; James et al., 2000). Flaxseed gum reduced blood-glucose response, as it behaved like a viscous fiber, while flaxseed protein interacted with the gums, as well as stimulated insulin secretion, reducing the glycemic response. Studies clearly showed flaxseed was an important functional food capable of slowing down the progression of many degenerative diseases (Oomah, 2001). A recent study by Bhathena and coworkers (2003) found flaxseed was more hypotriglyceridemic and hypocholesterolemic than soybean-protein concentrate. Consequently, flaxseed could provide an alternative, therapeutic treatment for individuals suffering from hypertriglyceridemia and hypercholesterolemia.
References
Allman, M.A., Pena, M.M., and Pang, D., Supplementation with flaxseed oil versus sunflower seed oil in healthy young men consuming a low fat diet: Effects on platelet composition and function, Eur. J. Clin. Nutr., 49:168–178, 1995.
Bhathena, S J., Ali, A.A., Haudenschild, C., Latham, P., Ranich, T., Mohamed, A.I., Hansen, C.T., and Velasquez, M.T., Dietary flaxseed meal is more protective than soy protein concentrate against hypertriglyceridemia and steatosis of the liver in an animal model of obesity, J. Am. Coll. Nutr., 22:157–164, 2003.
Caughey, G.E., Mantzioris, E., Gibson, R.A., Cleland, L.G., and James, M.J., The effect on human tumor necrosis factor alpha and interlukin-1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil, Am. J. Clin. Nutr., 63:116–122, 1996.
Cunnane, S.C., Ganguli, S., Menard, C., Liede, A.C., Hamadeh, M.J., Chen, Z.Y., Wolever, T., and Jenkins, D.J., High alpha-linolenic acid flaxseed (Linum usi-tatissimum): Some nutritional properties in humans, Br. J. Nutr., 69:443–453, 1993.
Dabrosin, C., Chen, J., Wang, L., and Thompson, L.U., Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth in human breast cancer xenografts, Cancer Lett., 185:31–37, 2002.
Ferretti, A. and Flanagan, V.P., Antithromboxane activity of dietary alpha-linolenic acid: A pilot study, Prostaglandins Leukot Essent. Fatty Acids, 54:451–455, 1996. Harris, R.K. and Haggerty, W.J., Assays for potentially anticarcinogenic phytochemicals in flaxseed, Cereal Foods World, 38:147–151, 1993.
James, M.J., Gibson, R.A., and Cleland, L.G., Dietary polyunsaturated fatty acids and inflammatory mediator production, Am. J. Clin. Nutr., 71: 343S-348S, 2000.
Jenkins, D.J., Kendall, C.W., Vidgen, E., Agarwal, S., Rao, A.V., Rosenberg, R.S., Diamandis, E.P., Novokmet, R., Mehling, C.C., Perera, T., Graffin, L.C., and Cunnane, S.C., Health aspects of partially defatted flaxseed including effects on serum lipids, oxidative measures, and ex vivo androgen and progestin activity: A controlled crossover trial, Am. J. Clin. Nutr., 69:395–402, 1999.
Li, D., Yee, J.A., Thompson, L.U., and Yan, L., Dietary supplementation with secoisolariciresinol diglycoside (SDG) reduces experimental metastasis of melanoma cells in mice, Cancer Lett., 142:91–96, 1999.
Oomah, D., Flaxseed as a functional food source, J. Sci. Food Agric., 81:889–894, 2001.
Rickard, S.E., Yuan, Y.V., and Thompson, L.U., Plasma insulin-like growth factor I levels in rats are reduced by dietary supplementation of flaxseed or its lignan secoisolariciresinol diglycoside, Cancer Lett., 161:47–55, 2000.
Yan, L., Yee, J.A., Li, D., McGuire, M.H., and Thompson, L.U., Dietary flaxseed supplementation and experimental metastasis of melanoma cells in mice, Cancer Lett., 124:181–186, 1998.
Folic acid
An important therapy for treating advanced colorectal and other cancers involves a combination of leucovorin and fluorouracil (Mini et al., 1990; Buroker et al., 1994; Trave et al., 1988). The potentiation between leucovorin and fluorouracil is associated with the formation of the metabolite methylenetetrahydrofolate (CH2FH4) (Dohden et al., 1993; Raghunathan et al., 1997) Since folic acid, an important B vitamin, can also elevate CH2FH4 levels, Raghunathan and Priest (1999) examined its ability to modulate the antitumor activity of fluorouracil. Implanted mouse mammary adenocarcinoma tumors were allowed to grow in mice maintained on a folic acid-depleted diet for 10 days. Folic acid (45 mg/kg) or fluorouracil (10 mg/kg) diluted in sterile saline solution were then injected i.p. The results in Table F.32 show that fluorouracil alone inhibited tumor growth by around 25 percent. In contrast, folic acid enhanced tumor growth almost twofold.
Folate. (Adapted from Park et al., Biomaterials, 26:1053–1061, 2005.)
TABLE F.32
Folic-Acid Potentiation of Flourouracil Antitumor Activity1
However, when folic acid was administered 4 h prior to fluorouracil, to maximize accumulation of CH2FHM4 and tetrahydrofolate (FH4), tumor growth was significantly (p<0.001) reduced by more than 70 percent. This study confirmed the ability of folic acid to potentiate the antitumor effects of fluorouracil. Folate status is now recognized as a factor in the prevention of carcinogenesis (Kim, 1999). A deficiency in folate is thought to increase the risk of malignancy by either DNA hypomethylation and proto-oncongene activation or by inducing uracil misincorporation, resulting in DNA breakage and chromosomal damage (Duthie, 1999). Recent studies pointed to an association between higher dietary folate and reduced breast-cancer risk in women with high alcohol intake (Zhang et al., 1999; Rohan et al., 2000; Negri et al., 2000; Sellers et al., 2001). The primary circulating form of folate is 5-methyl-enetetrahydrofolate, which is produced from 5,10-methylenetetrahydrofolate by the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). In a case-control study with 62 women, Sharp et al. (2002) showed MTHFR polymorphisms may be modifiers of the relationship between dietary folate and breast cancer. While the number of subjects in this study was small, there was a trend between increasing folate intake and decrease in the risk of breast cancer. A recent study by Plaschke et al. (2003), however, was unable to find a similar association between high MTHFR activity and colorectal cancer.
References
Buroker, T.R., O’Connell, M.J., Wieand, H.S., Krook, J.E., Gerstner, J.B., Mailliard, J.A., Schaefer, P.L., Levitt, R., Kardinal, C.G., and Gesme, D.H., Jr., Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer, J. Clin. Oncol., 12:14–20, 1994.
Dohden, K., Ohmura, K., and Watanabe, Y., Ternary complex formation and reduced folate in surgical specimens of human adenocarcinoma tissues, Cancer, 71:471–480, 1993.
Duthie, S.J., Folic acid instability and cancer: Mechanisms of DNA stability. Br. Med. Bull. 55:578–592, 1999.
Kim, Y.I., Folate and cancer prevention: A new medical application of folate beyond hyperhomocysteinemia and neural tube defects, Nutr. Rev., 57:314–321, 1999.
Mini, E., Trave, F., Rustum, Y.M., and Bertino, J.R., Enhancement of the antitumor effects of 5- fluorouracil by folinic acid, Pharmacol. Ther., 47:1–19, 1990.
Negri, E., La Vecchia, C., and Franceschi, S., Re: Dietary folate consumption and breast cancer risk, J. Natl. Cancer Inst., 92:1270–1271, 2000.
Park, E.K., Lee, S.B., and Lee, Y.M., Preparation and characterization of methoxy poly(ethylene glycol)/ poly(ε-coprolactone) amphiphilic block copolymeric nanospheres for tumor specific folate-mediated targeting of anticancer drugs, Biomaterials, 26:1053–1061, 2005.
Plaschke, J., Schwanebeck, U., Pistorius, S., Saeger, H.D., and Schackert, H.K., Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and hereditary colorectal cancer with or without microsatellite instability, Cancer Lett., 191:179–185, 2003.
Raghunathan, K. and Priest, D.G., Modulation of fluorouracil antitumor activity by folic acid in a murine model system, Biochem. Pharmacol., 58: 835–839, 1999.
Raghunathan, K., Schmitz, J.C., and Priest, D.G., Impact of schedule on leucovorin potentiation of fluorouracil antitumor activity in dietary folic acid depleted mice, Biochem. Pharmacol., 53:1197–1202, 1997.
Rohan, T.E., Jain, M.G., Howe, G.R., and Miller, A.B., Dietary folate consumption and breast cancer risk, J. Natl. Cancer Inst., 92:266–269, 2000.
Sellers, T.A., Kushi, L.H., Cerhan, J.R., Vierkant, R.A., Gapstur, S.M., Vachon, C.M., Olson, J.E., Therneau, T.M., and Folsom, A.R., Dietary folate intake, alcohol, and risk of breast cancer in a study of postmenopausal women, Epidemiology, 12:420–428, 2001.
Sharp, L., Little, J., Schofield, A.C., Pavlidou, E., Cotton, S.C., Miedzybrodzka, Z., Baird, J.O.C., Haites, N.E., Heys, S.D., and Grubb, D.A., Folate and breast cancer: Role of polymorphisms in methylene-tetrahydrofolate reductase (MTHFR), Cancer Lett., 181:65–71, 2003.
Trave, F., Rustum, Y.M., Petrelli, N.J., Herrera, L., Mittleman, A., Frank, C., and Creaven, P.J., Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluorouracil in patients with advanced colorectal carcinoma, J. Clin. Oncol., 6:1184–1191, 1988.
Zhang, S., Hunter, D.J., Hankinson, S.E., Giovannucci, E.L., Rosner, B.A., Colditz, G.A., Speizer, F.E., and Willett, W.C., A prospective study of folate intake and the risk of breast cancer, J. Am. Med. Assoc., 281:1632–1637, 1999.
Foxglove (Digitalis purpurea)
Foxglove first came into prominence more than 200 years ago when William Withering reported the efficacy of its leaves in treating congestive heart failure. Subsequent work, using the flouometric microculture cytoxicity assay, isolated a relatively high-molecular-weight fraction in the ethanolic extract of foxglove with potent antitumor activity (FMCA) (Larsson et al, 1992). This fraction was identified as digitoxin, a steroidal compound characterized by a five-membered, unsaturated lactone ring, belonging to a group of cardiac glycosides known as cardenolides. Another member of this group is digoxin. A second group of cardiac glycosides containing a six-membered, unsaturated lactone ring was also identified and referred to as bufadienolides. Of the latter, the therapeutically most important one is proscillardin A. Digitalis, or cardiac glycosides, refer to any steroidal glycoside compounds that cause characteristic positively inotropic (increase in maximum and velocity of myocardial contractile force associated with prolongation of relaxation period) and electrophysiological effects on the heart. Evidence strongly suggests that cardiac glycosides induce increases in intracellular Na+ concentration or activity in which digitalis induces a positive inotropic effect.
The first large-scale, placebo-controlled mortality study to examine the effect of digoxin on 7788 patients suffering from chronic heart failure was conducted by Gheorghiade (1997). While digoxin had no effect on their survival, over 37 months of follow-up, the incidences of hospitalization due to worsening of heart failure were significantly lower in patients receiving digoxin compared to the placebo. Digoxin, the most commonly prescribed of the various cardiac glycoside preparations, was reported by Hauptman (1999) to be still useful for treating heart failure. Using primary cultures of tumor cells from patients and a human cell-line panel, Johansson et al. (2001) evaluated the cytotoxicity of five cardiac glycosides plus the saponin digitoxin and its aglycone digitoxigenin. Marked differences were observed among the different cardiac glycosides, with respect to their toxicities. Proscillaridin A proved to be the most potent in 9 of 10 human tumor lines, confirming the literature that cardenolides are weaker than the corresponding bufadienolides. The order of potency, after proscillaridin A, was digitoxin, ouabain, digoxin, lanatoside C, digitoxigenin, and digitonin, which paralleled their inhibitory potency on Na+/K+M-transporting ATPase from human cardiac muscle reported previously for cardiac glycosides by Schonfeld et al. (1986). Reviewing the use of digitoxin as a treatment of congestive heart failure, Beltz et al. (2001) showed digitoxin exerted the same pharmacodynamic kinetics as digoxin. However, digitoxin was more lipophilic than digoxin, giving it a more stable pharmacokinetic profile and a lower incidence of toxic side effects. Roever and coworkers (2000) had shown previously that digitoxin had a lower rate of toxicity compared to digoxin when used by elderly patients. Patients taking digoxin had three times the odds of experiencing toxicity compared to digitoxin.
Structure of digitoxin. (From Hage and Sengupta, J. Chromatogr. B., 724:91–100, 1999. With permission.)
Cardiac glycosides can interact with other drugs, so caution must be exercised when introducing new pharmaceuticals. For example, quinidine inhibited the transport of digoxin across the cell membranes, particularly in the kidneys (Fromm et al., 2002), while amiodarone increased the steady state of digoxin so that dosages could be decreased by as much as 50 percent.
References
Beltz, G.G., Breithaupt-Grogler, K., and Osowski, U., Treatment of congestive heart failure— current status of use of digitoxin, Eur. J. Clin. Inv., 31(Suppl. 2): 10–17, 2001.
Fromm, M.F., Kim, R.B., Stein, C.M., Wilkinson, G.R., and Roden, D.M., Inhibition of Pglycoproteinmediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine, Circulation, 2002 (in press).
Gheorghiade, M., Digitoxin therapy in chronic heart disease, Cardiovasc. Drugs Ther., 11:279– 283, 1997.
Hage, D.S. and Sengupta, A., Characterisation of the binding of digitoxin and acetyldigitoxin to human serum albumin by high-performance affinity chromatography, J. Chromatogr. B., 724:91–100, 1999.
Hauptmann, P.J., Digitalis, Circulation, 99:1265–1270, 1999.
Johansson, S., Lindholm, P., Gullbo, J., Larsson, R., Bohlin, L., and Claeson, P., Cytotoxicity of digitoxin and related glycosides in human tumor cells, Anticanc. Drugs, 12:475–483, 2001.
Larsson, R., Kristensen, J., Sandberg, C., and Nygren, P., Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemias using a fluorescent microculture cytoxicity assay (FMCA), Int. J. Cancer, 50:177–185, 1992.
Roever, C., Ferrante, J., Gonzalez, E.C., and Roetzheim, R.G., Comparing the toxicity of digoxin and digitoxin in a geriatric population: Should an old drug be rediscovered, South. Med. J., 93:5–15, 2000.
Schonfeld, W., Schonfeld, R., Menke, K.H., Weiland, J., and Repke, K.R.H., Origin of differences of inhibitory potency of cardiac glycosides in Na+/K+ transporting ATPase from human cardiac muscle, human brain cortex and guinea-pig cardiac muscles, Anticacer. Drugs, 12:475–483, 1986.
Fruits
see also Individual fruits A large number of epidemiological studies have associated the low incidence of common cancers, cardiovascular disease, and other chronic diseases to the high consumption of fruits and vegetables (Ness and Powles, 1997; Steinmetz and Potter, 1996). Lampe (1999) reviewed the many human studies in which phytochemicals identified in fruits and vegetables were investigated in an effort to assess their mechanisms of action. A large, prospective, cohort study of 39,876 female health professionals over a five-year period by Liu and coworkers (2000) indicated that a higher intake of fruits and vegetables may have a protective effect against cardiovascular disease. This is attributed to the naturally occurring antioxidants scavenging free radicals and preventing degenerative diseases, such as cancer, atherosclerosis, diabetes, and arthritis (Kaur and Kapoor, 2001). Thompson and coworkers (1999) showed that increased consumption of fruits and vegetables by a group of women significantly decreased the levels of urinary 8-hydroxydeoxy-guanosine (8 OhdG), malondialdehyde (MDA), and 8-isoprostane F-2α, all markers of oxidative cellular damage. The data generated by this study showed that increased fruit and vegetable consumption did in fact reduce cellular injury, as measured by these biomarkers. Broekmans et al. (2000) were the first to demonstrate that fruits and vegetables with moderate folate levels decrease plasma homocysteine, a risk factor for cardiovascular disease.
References
Broekmans, W.M.R., Klopping-Ketelaars, I.A.A., Shuurman, C.R., Verhagen, H., vab den Berg, H., Kok, F.J., and van Poppel, G., Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans, J. Nutr., 130: 1578–1583, 2000.
Kaur, C. and Kapoor, H.C., Antioxidants in fruits and vegetables—the millennium’s health, Int. J. Food Sci. Technol., 36:703–725, 2001.
Lampe, J.W., Health effects of vegetables and fruit: Assessing mechanisms of action in human experi mental studies, Am. J. Clin. Nutr., 70:475S-490S, 1999.
Liu, S., Manson, J.E., Lee, I.-M., Cole, S.R., Hennekens, C.H., Willett, W.C., and Buring, J.E., Fruit and vegetable intake and risk of cardiovascular disease: The Women’s Health Study, Am. J. Clin. Nutr., 72:922–928, 2000.
Ness, A.R. and Powles, J.W., Fruit and vegetables, and cardiovascular disease: A review, Int. J. Epidemiol., 26:1–13, 1997.
Steinmetz, K.A. and Potter, J.D., Vegetable, fruit, and cancer prevention: A review, J. Am. Diet. Assoc., 96: 1027–1039, 1996.
Thompson, H.J., Heimendinger, J., Haegele, A., Sedlacek, S.M., Gillete, C., O’Neille, C., Wolfe, P., and Corny, C., Effect of increased vegetable and fruit consumption on markers of oxidative cellular damage, Carcinogenesis, 20:2261–2266, 1999.