Estrogens and environmental estrogens

Estrogens and environmental estrogens

Biomed Pharmacother 2002 ; 56 : 36-44 © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S075333220100155X/REV Review Estr...

162KB Sizes 0 Downloads 194 Views

Biomed Pharmacother 2002 ; 56 : 36-44 © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S075333220100155X/REV

Review

Estrogens and environmental estrogens H. Tapiero1*, G. Nguyen Ba1, K.D. Tew2 1

Laboratoire de Pharmacologie Cellulaire & Moléculaire, CNRS UMR 8612, Université de Paris Sud, Faculté de Pharmacie, 5, rue Jean-Baptiste Clément, 94200 Chatenay Malabry, France; 2Fox Chase Cancer Center, Philadelphia, PA, USA (Received and accepted 21 November 2001)

Summary – The natural female sex hormone estrogens binds once inside the cell to a protein receptor to form a ‘ligand-hormone receptor complex’. The binding activates the hormone receptor, which triggers specific cellular processes. The activated hormone receptor then turns on specific genes, causing cellular changes that lead to responses typical of a ligand-hormone receptor complex. Estrogens (especially estradiol) bring out the feminine characteristics, control reproductive cycles and pregnancy, influence skin, bone, the cardiovascular system and immunity. Natural hormones are more potent than any of the known synthetic environmental estrogens (except drugs such as diethylstilbestrol [DES]). Estrogen production varies according to different factors (gender, age and reproductive cycles). Women produce more estrogen than men and the production is more abundant during fetal development than in the postmenopausal period. Most natural estrogens are short-lived, do not accumulate in tissue and are easily broken down in the liver. In contrast to natural estrogens, estrogenic drugs such as ethynylestradiol diethylstilbestrol (DES), synthetic environmental estrogens such as ß-hexachlorocyclohexane (ß-HCH), polychlorinated biphenyls (PCBs), o, p, p’DDT, 4-nonylphenol (NP) and phytoestrogens such as isoflavones or lignans, are more stable and remain in the body longer than natural estrogens. Because most of these compounds are lipophilic, they tend to accumulate within the fat and tissue of animals and humans. Thus, depending on the natural estrogen levels, environmental estrogens may have different influences (mimicking, blocking or cancelling out estrogen’s effects) on estrogen activities. © 2002 Éditions scientifiques et médicales Elsevier SAS chemicals / estrogens / isoflavones / lignans / phytoestrogens

ESTROGENS Estrogens (figure 1) suppress ovulation and with progesterogens form the basis of combined oral contraceptives and hormone replacement therapy (HRT). They are also used to supplement natural estrogen levels where these are insufficient as in some menstrual disorders and to suppress androgen formation and thus tumour growth of cancers dependent on androgens (prostate cancers). Estrogens appear to

*Correspondence and reprints. E-mail address: [email protected] (H. Tapiero).

offer a number of beneficial effects to women including protection against osteoporosis and heart attacks. Some cancers (breast and uterine cancers) are dependent on a supply of estrogen for growth especially during the early stage so high estrogen levels are detrimental. A success in treating breast cancer has been the introduction of tamoxifen which contains the stilbene skeleton seen in diethylstilbestrol and related estrogens but acts as an estrogen-receptor antagonist rather than as an agonist in breast tissue, and deprives the cells of estrogen. However it is an agonist in bone and uterine tissue. Estrogen antagonist can also be used as a fertility drug, occupying estrogen receptors and interfering with feedback mechanisms. Clo

Estrogens and environmental estrogens

37

Figure 1. Estrogens have an aromatic A ring, basic C18 skeleton estrane and no carbon side-chain at C17: estradiol, the principal and most potent. Low levels are found in urine. Estrone and the 16α-hydroxylated derivative estriol are less active metabolites found in larger amounts in urine. Estrone has also been found in some plant seeds.

miphene and to a lesser extent tamoxifen (figure 2) are used in this way, but can lead to multiple pregnancies. ENVIRONMENTAL ESTROGENS ‘Environmental estrogens’are a diverse group of synthetic chemicals and natural plant compounds that may act like estrogen hormones in animal and humans. They cannot be identified by structure alone and this makes it hard to predict which natural and synthetic chemicals will act like estrogenic hormones in living organisms (figure 3). CHEMICAL ESTROGENIC COMPOUNDS Estrogenic compounds are found in many synthetic chemicals produced for specific purposes [1-3]: insecticides (o, p’-DDT, endosulfan, dieldrin, methoxychlor, kepone, dicofol, toxaphene or chlordane);

herbicides (alachlor, atrazine or nitrofen); fungicides (benomyl, mancozeb or tributyl tin); nematocides (aldicarb and dibromochloropropane); industrial chemicals (polychlorinated biphenyls (PCBs) dioxin and benz (a) pyrene); heavy metals (lead, mercury, cadmium); household products (breakdown products of detergents and associated surfactants including nonylphenol and octylphenol); products associated with plastics (bisphenol A, phtalates) or in pharmaceuticals (DES, cimetidine). How do substances with strikingly different chemical structures as natural hormones produce similar physiological results as natural estrogens? Although natural steroid hormones generally function by binding to specific receptor sites, ‘environmental estrogens’ can affect the hormonal system in a number of different ways. Once the compound is bound to the receptor, the mimicker can either: – produce a normal hormone response;

38

H. Tapiero et al.

Figure 2. Estrogen receptor antagonists. Tamoxifen contains the stilbene skeleton seen in diethylstilbestrol and related estrogens. Toremifene is used primarily in postmenopausal women. Clomiphene lead to ova release by occupying estrogens receptors and interfering with feed back mechanisms. Can lead to multiple pregnancies.

– cause an abnormal response or elicit no response as it blocks the receptor site and prevents natural hormones from binding; – bind to other receptors and create a novel reaction or interfere indirectly with normal hormonal action; or – alter production and breakdown of hormone receptors and natural hormones modifying the endocrine responses. Thus, the multiple signaling pathways initiated at or below levels found in human breast cancer or fat tissue (ß-hexachlorocyclohexane &[bgr;-HCH] or p, p’DDT) can lead to cell division by influencing the estrogen receptor without binding to it. In addition, compound such as p, p’DDT can also bind to androgen receptor and inhibit androgen binding [4-7]). ISOFLAVONOIDS AND LIGNANS

Figure 3. Environmental compounds.

estrogens.

Chemical

estrogenic

Isoflavonoids are almost entirely restricted to the plant family Leguminosae/Fabaceae. Many hundreds of different isoflavonoids have been identified. At least 20 compounds have been identified in at least 300 plants from more than 16 different plant families. The two most studied groups of phytoestrogens [8-11] are the isoflavones (figure 4) (found in soybeans and other plants) [12-15] and lignans present in foodstuffs, including flaxseed and cereals. Interest has been directed toward the products of intestinal microbial breakdown of lignan compound enterodiol and enterolactone (figure 5) [16-18]. Some of the many variants of Pterocarpans such as medicarpin

Estrogens and environmental estrogens

39

a)

Figure 4. Chemical structures of various isoflavones.

b) Figure 6. a). Isoflavonoids compounds: isoflavones (daidzein, formononetin), pterocarpans (medicarpin) and coumestans (coumestrol). b). Biosynthesis of pterocarpans (medicarpin, pisatin, which have antifungal activity) and rotenone, which is are powerful insecticidal and pisticidal (fish poison) agents interfering with oxidative phosphorylation) from the isoflavone formononetin.

Figure 5. The lignans: enterodiol and enterolactone are derived from dietary plant lignans, particularly secoisolariciresinol diglucoside, by the action of intestinal microflora.

from Lucerne (Medicago sativa) and pisatin from pea (Pisum sativum) (figure 6) have antifungal activity and form part of these plants’ natural defence mechanism against fungal attack. Simple isoflavones (daidzein) and coumestans (coumestrol) from Lucerne and clovers (Trifolium pratense) have sufficient estrogenic activity to seriously affect the reproduction of grazing animals and are termed phytoestrogens. These planar molecules mimic the shape and polarity of the steroid hormone estradiol. In the human

diet, soya (Glycine max) products are believed to give some protection against estrogen-dependent cancers such as breast cancer, by restricting the availability of the natural hormone. The phytoestrogens are being synthesized in plants from phenylpropanoids and simple phenols [19]. Molecular modelling studies show the 4’-hydroxyl on the B ring of isoflavones to be the binding site for the estrogen receptor [20, 21]. Formononetin and Biochanin A show extremely poor affinity for the estrogen receptor due to the presence of methoxylated group in the B ring (figure 4), which is rapidly and efficiently demethylated, giving rise to daidzein and genistein, respectively.

40

H. Tapiero et al.

Phytoestrogens that bind to the estrogen receptor can act as estrogen agonists or antagonists [22-26]. However, as compared to estradiol or estrone ‘dietary estrogens’ are weakly estrogenic [27-31]. Their actions at the cellular and molecular level depend on their concentration, receptor status, the concentration of endogenous estrogens and the type of target organ or cell. The preferential binding of nonsteroidal estrogens to the Erβ receptor (mainly distributed in bone, brain, vascular endothelial and bladder) suggests that they may exert their action through separate pathways from those of classical steroidal estrogens [32, 33]. In addition, phytoestrogens exhibit other activities such as antioxidant [34-39], antiproliferative [40, 41] and antiangiogenic [42, 43] activities. Growth factors [44, 45] and cytokines play a role in regulating osteoclast activity [46], and several of these are tyrosine kinase-mediated pathways that could conceivably be influenced by genistein. All these effects may contribute to the effectiveness of isoflavones as potential anticancer agents. Tamoxifen (figure 2) is now in use as a prophylactic for the prevention of breast cancer in high-risk women [47, 48]. Genistein was suggested as an effective nonpharmacologic alternative for disease prevention in such women [49] and in prostatic cancer. In vitro studies showed that genistein inhibits the growth of cultured prostate cells [45]. Because oxidative modification of LDL is an important mechanism in atherosclerosis, the antioxidant properties of isoflavones was reported [34-39] and shown to play a role in lowering serum cholesterol [50-52], total LDL and may reduce the extent of lipid peroxidation. However, there are multiple mechanisms by which the isoflavones might prevent the development of atherosclerosis [53]. They may bind to estrogen receptors and act as estrogen agonists and/or act as tyrosine kinase inhibitors and it is known that cardiovascular protection might be mediated by this mechanism. Recently, another potential mechanism relates to isoflavone ability to inhibit in vitro the migration and proliferation of smooth muscle cells which are important in promotion and progression of the atherosclerotic process [54]. Genistein has been shown to suppress thrombus formation by inhibiting platelet activation [55, 56] and aggregation [57, 58]. Several isoflavones and lignans were found to inhibit the activity of the 5α-

reductase, an enzyme important in androgen metabolism in human genital skin fibroblasts and prostatic tissue [59, 60]. Most of the phytoestrogens are of dietary origin and are usually found as glycosides. When consumed by humans, the glycosides are probably hydrolyzed in part by gastric acid and extensively biotransformed in the intestine by the action of bacterial glucosidases which release the aglycones. Hydrolyzed glycosides can be absorbed from the intestinal lumen or further metabolized to many specific metabolites including equol (the main end product of bacterial degradation of daidzein) and 4-ethylphenol (the main end-product from genistein) [49, 61-63]. After consumption of foods containing isoflavones, genistein, daidzein and their metabolites are found in urine. Wide individual variations were seen in urinary isoflavonoid phytoestrogen excretion. In women equol excretion was associated with higher intake of dietary fiber and carbohydrates [64]. Since the binding affinity of equol for the estrogen receptor and its estrogen potency is greater than that of its precursor daidzein [65], it might therefore be advantages to improve the intestinal conversion of daidzein to equol. Thus, the makeup of the diet can alter the metabolism of isoflavones in the intestine. It was found that under a high carbohydrate environment, fermentation was stimulated and this increased the rate of conversion of daidzein to equol [66, 67]. This suggests that the overall composition of the diet may have to be taken into consideration in clinical studies investigating the potential efficacy of isoflavones, and the extent of intestinal bacterial metabolism will therefore determine the bioavailability of dietary estrogens and influence the potential for physiologic effect. Along with steroid hormone metabolism [68, 69] the liver probably plays a key role in the further metabolism of isoflavones by conjugating the aglycone with glucuronic acid [70-72]. The efficiency of conjugation of isoflavones is high and consequently the proportion of circulating free isoflavones is small. In human diet, genistein (4’,5,7, -trihydroxyisoflavone) and daidzein (7-β-glucoside) (figure 4) are the predominant isoflavones in soybeans. It was initially believed that their action would be predominantly hormonal and it might prevent hormonedependent breast and prostate cancers by virtue of their potential estrogen antagonist activity [73-75]. However, in cell culture, when 17β-estradiol was

Estrogens and environmental estrogens

added at physiologic concentration (0.3 nmol/L) to the media, cell growth was highly stimulated. Addition of genistein to the media at high concentrations (> 5 µmol/L) caused a dose-dependent reduction in 17β-estradiol-stimulated cell proliferation [44, 45, 76, 77]. Thus, it was suggested that they may inhibit proliferation by mechanisms other than the classical estrogen receptor-mediated pathway and no single action can explain the in vitro and in vivo effects of isoflavones [45, 78-82]. Genistein is a specific inhibitor of protein tyrosine kinase (PTK) and it inhibits the EGF receptor (EGF-R) PTK activity in vitro [78]. In addition to its PTK-inhibitory activity, genistein has also been shown to inhibit cell cycle progression by interfering with signal transduction pathways [83, 84]. In the in vitro studies it was shown that genistein inhibits the growth of prostate cancer cells [85] without inhibiting epidermal growth factor receptor autophosphorylation [45]. Cells going through the G1/S transition can be also prevented by TGFβ1, a member of the TGF growth factors that attenuates passage through cell cycle checkpoints, predominantly G1/S via transcriptional regulation proteins [86]. Tamoxifen, an estrogen antagonist, induces TGFβ1 in the human breast cancer MCF7 cells [87, 88] and in breast cancer in vivo [89]. Growth inhibition effects which were observed similarly for genistein and tamoxifen correlated with increased amounts of TGFβ1 in the culture medium and were blocked by antibodies against TGFβ1 added exogenously to the culture medium [90]. Moreover, exposure of Human Mammary Epithelial (HME) cells to genistein caused either synthesis and secretion of TGFβ1or the secretion of a preexisting intracellular pool of TGFβ1. Since the reduction in bone loss after ovariectomy is prevented by the administration of estrogens and attenuated by the administration of genistein, it was suggested that in bone as in HME cells, enhancement of TGFβ1 activity could be the basis for the action of genistein and considered to be related to the estrogenic mode of action of genistein [91, 92]. In addition, abnormally low TGFβ1 concentrations were observed in atherosclerosis pathology, and cardio-protection afforded by the genistein involves an induction of TGFβ1similar to that observed in HME cells [93-95]. The role of genistein in gene transcription levels has been related to its enhancement of TGFβ1 [96]. Studies on the pathogenesis of cystic fibrosis lung

41

disease in human bronchial epithelial cells showed that increased transcriptional of the mucin gene (MUC2) by Pseudomonas aeruginosa lipopolysaccharide could be blocked by genistein and the tyrosine kinase inhibitor tyrphotsin AG126 [97, 98]. In addition, it has been shown that genistein inhibits DNA topoisomerases I and II [99, 100], prevents hepatic injury caused by the release of inflammatory cytokines during ischemia and reperfusion [101], inhibits oxidative DNA damage induced by ultraviolet light [102] and due to its antioxidant capacity inhibits lipid oxidation in vitro [103, 104] and angiogenesis [42, 105]. Biochanin A (4’-methoxygenistein), another isoflavone present in large amounts in subterranean clover, is shown to be a weak protein kinase inhibitor in vitro [106]. It nonetheless is an inhibitor of growth factor-stimulated cell growth of breast cancer [107] and prostate [45] cell lines. Although some in vitro data suggest that soybeanderived isoflavones may have anticarcinogenic activity, there is less evidence for an in vivo effect of these agents in a pure form [108]. Anticarcinogenic activity was mostly attributed to the Bowman-Birk inhibitor (BBI), a soybean-derived serine protease inhibitor and a potential cancer chemopreventive agent [109] for humans which was identified by Bowman [110] and purified by Birk [111]. BBI is a protein of a molecular weight of 8000 constituted of 71 amino acids with two separate protease inhibitory sites for trypsin and chymotrypsin. Although the anticarcinogenic activity of BBI is still unknown it has been localized to the chymotrypsin inhibitory region of the protein molecule [112]. One of the contributing mechanisms for the BBI anticarcinogenic activity is a selective toxicity for premalignant and certain malignant cells [109]. Because inflammation is closely associated with carcinogenesis, the antiinflammatory activity of BBI could be the major mechanism by which BBI prevents carcinogenesis [109]. Indeed, it was reported that anticarcinogenic protease inhibitors prevent the release of the superoxide anion radical and hydrogen peroxide from polymorphonuclear leukocytes and other cell types stimulated with tumor promoting agents [113, 114]. BBI can keep free radicals from being produced in cells and thereby decrease the amount of oxidative damage [115].

42

H. Tapiero et al.

ACKNOWLEDGEMENTS This study was sponsored in part by the Professor Association Company (PAC), Madrid Spain and P.A.N. This review is part of the dossier that will be published in the next issue of Biomedicine & Pharmacotherapy dedicated to “Steroid receptors” (Biomed Pharmacol 2002 ; 56 : n° 2). REFERENCES 1 Bergeron JM, Crews D, McLachlan JA. PCBs as environmental estrogens: turtle sex determination as a biomarker of environmental contamination. Environ Health Perspect 1994 ; 102 : 780-1. 2 Safe S. Environmental and dietary estrogens and human health. Environ Health Perspect 1995 ; 103 : 346-51. 3 DeRosa C, Richter P, Pohl H, Jones D. Environmental exposures that affect the endocrine system: Public health implications. J Toxicol Environ Health 1998 ; 1 : 3-26. 4 Coosen R, van Velson FL. Effects of the ß-isomer of hexacholocyclohexane on estrogen-sensitive human mammary tumor cells. Toxicol Appl Pharmacol 1989 ; 101 : 310-8. 5 Steinmetz R, Young PCM, Caperell-Grant A, Gize EA, Madhukar BV, Ben-Jonathan N, et al. Novel estrogenic action of the pesticide residue β-hexachlorocyclohexane in human breast cancer cells. Cancer Res 1996 ; 56 : 5403-9. 6 Shen K, Novak RF. DDT stimulates c-erbB2, c-met and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation and proliferation of human breast epithelial cells. Biochem Biophys Res Commun 1997 ; 231 : 17-21. 7 Kelce WR, Stone CR, Laws SC, Gray LE, Kempainen JA, Wilson EM. Persistent DDT metabolite p, p’DDE is a potent androgen receptor antagonist. Nature 1995 ; 375 : 581-5. 8 Cheng E, Yoder L, Story CD, Burrough W. Estrogenic activity of some isoflavone derivatives. Science 1954 ; 120 : 575-6. 9 Setchell KDR. Naturally occurring non-steroidal estrogens of dietary origin In : Mc Lachlan J, Ed. Estrogens in the environment: influence on the development. New York: Elsevier Science ; 1985. 69-85. 10 Price KR. Fenwick GR Naturally occurring estrogens in foods: a review. Food Addit Contam 1985 ; 2 : 73-106. 11 Setchell KDR. Phytoestrogens: the biochemistry, physiology and implications for human health of Soy isoflavones. Am J Clin Nutr 1998 ; 68 : 1333S-46S. 12 Walz E. Isoflavone: a saponin glucoside in sya. Justus Liebigs Ann Chem 1931 ; 489 : 118-55. 13 Naim M, Gestetner B, Zilkah S, Birk Bondi YA. Soybean isoflavones, Characterization determination and antifungal activity. J. Agric Food Chem. 1974 ; 22 : 806-10. 14 Eldridge AC. Determination of isoflavones in soybean flours, protein concentrates and isolates. J Agric Food Chem 1982 ; 30 : 353-5. 15 Wang H- J, Murphy PA. Isoflavone content in commercial soybean foods. J Agric Food Chem 1994 ; 42 : 1666-73. 16 Axelson M, Sjovall J, Gustafsson BE, Setchell KDR. Origin of lignans in mammals and identification of a precursor from plants. Nature 1982 ; 298 : 659-60. 17 Setchell KDR. Discovery and potential clinical importance of mammalian lignans. In: Cunnane SS, Thompson LU, Eds. Flaxseed in human nutrition. Champaign, IL: AOCS Press; 1995. p. 82-98.

18 Setchell KDR, Lawson AM, Mitchell FL, Adlercreutz H, Kirk DN, Axelson M. Lignans in man and animal species. Nature (Lond.) 1980 ; 287 : 740-2. 19 Hahlbrock K. Flavonoids. In: Conn E, Ed. The biochemistry of plants: a comprehensive treatise-secondary plant products. New York: Academic Press; 1981. p. 425-56. 20 Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997 ; 389 : 753-8. 21 Pike AC, Brzozowski AM, Hubbard R, Bonn T, Thorsell AG, Engstrom O, et al. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 1999 ; 18 : 4608-18. 22 Shemesh M, Lindner HR, Ayalon N. Affinity of rabbit uterine estradiol receptor for phytoestrogens and its use in a competitive protein binding radioassay for plasma coumestrol. J Reprod Fertil 1972 ; 20 : 1-9. 23 Verdeal K, Brown RR, Richardson T. Ryan DS Affinity of phytoestrogen for estradiol-binding proteins and effect of coumestrol on growth of 7,12-dimethylben [a] anthracene induced rat mammary tumors. J Natl Cancer Inst 1980 ; 64 : 285-90. 24 Barnes S, Peterson TG. Biochemical targets of the isoflavone genistein in tumor cell lines. Proc Soc Exp Biol Med 1995 ; 208 : 103-8. 25 Makela S, Pylkkanen LH, Santti RS, Adlercreuz H. Dietary soybean may be antiestrogenic in male mice. J Nutr 1994 ; 125 : 437-45. 26 Makela S, Santti RS, Salo L, McLachlan JA. Phytoestrogens are partial estrogen agonists in the adult male mouse. Environ Health Perspect 1995 ; 103 : 123-7. 27 Martin PM, Horwitz KB, Ryan DS, McGuire WL. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 1978 ; 103 : 1860-7. 28 Tang BY. Adams NR The effect of equol on estrogen receptors and on synthesis of DNA and protein in immature rat uterus. J Endocrinol 1980 ; 85 : 291-7. 29 Farmakalidis E, Hathcock JN, Murphy PA. Estrogenic potency of genistin and daidzin in mice. Food Chem Toxicol 1985 ; 23 : 741-5. 30 Markiewicz L, Garey J, Adlercreuz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol 1993 ; 45 : 399-405. 31 Molteni A, Brizio-Molteni L, Persky V. In vitro hormonal effects of soybean isoflavones. J. Nutr 1995 ; 125 : 751S-6S. 32 Kuiper GGJM, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997 ; 138 : 863-70. 33 Paech K, Webb P, Kuiper GGJ, Nilsson S, Gustafsson JA, Kushner PJ, et al. Differential ligand activation of estrogen receptors ER and ERβ at AP1 sites. Science (Washington, DC) 1997 ; 277 : 1508-10. 34 Gyorgy P, Murata K, Ikehata H. Antioxidants isolated from fermented soybeans. Nature 1964 ; 203 : 870-2. 35 Jha HC, Von Recklinghausen G, Zilliken F. Inhibition of in vitro microsomal lipid peroxidation by isoflavonoids. Biochem Pharmacol 1985 ; 34 : 1367-9. 36 Wei H, Bowen R, Cai Q, Barnes S, Wang Y. Antioxidant and antiproliferative effects of the soybean isoflavone genistein. Proc Soc Exp Biol Med 1995 ; 208 : 124-30. 37 Bowen R, Cai Q, Rahn RO. Inhibition of UV light – and Fenton reaction-induced oxidative DNA damage by the soybean isoflavone genistein. Carcinogenesis 1996 ; 17 : 73-7. 38 Ruiz-Larrea MB, Mohan AR, Paganga G, Miller NJ, Bolwell GP, Rice Evans CA. Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res 1997 ; 26 : 63-70.

Estrogens and environmental estrogens

39 Kapiotis S, Hermann M, Held I, Seelos C, Erhinger H, Gmeiner BMK. Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL. Arterioscler Thromb Vasc Biol 1997 ; 17 : 2868-74. 40 Hirano T, Oka K, Akiba M. Antiproliferative activity of synthetic and naturally occurring flavonoids on tumor cells of the human breast carcinoma cell line ZR-75-1. Res Commun Chem Pathol Pharmacol 1989 ; 64 : 69-78. 41 Yanagihara K, Ito A, Toge T, Numoto M. Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res 1993 ; 53 : 581521. 42 Fotsis T, Peper M, Adlercreutz H, Fleischmann G, Hase T, Montesano R, et al. Genistein, a dietary derived inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1993 ; 90 : 2690-4. 43 Jaggers DC, Collins WP, Milligan SR. Potent inhibitory effects of steroids in an in vitro model of angiogenesis. J. Endocrinol 1996 ; 150 : 457-64. 44 Peterson TG, Barnes S. Genistein inhibits both estrogen and growth factor stimulated proliferation of human breast cancer cells. Cell Growth Differ 1996 ; 7 : 1345-51. 45 Peterson TG, Barnes S. Genistein and Biochanin A inhibit the growth of human prostate cancer cells in culture but not epidermal growth factor receptor tyrosine phosphorylation. Prostate 1993 ; 22 : 335-45. 46 Manolagas SC, Jilka R. Bone marrow, cytokines and bone remodeling. N Engl J Med 1995 ; 332 : 305-11. 47 Powles TJ. Chemoprevention of breast cancer using tamoxifen. Endocrinol Relat Cancer 1997 ; 4 : 255-60. 48 Jordan VC. Tamoxifen: the herald of a new era of preventive therapeutics. J Natl Cancer Inst 1997 ; 89 : 747-9. 49 Kelly GE, Joannou GE, Nelson C, Reeder AY, Waring MA. The variable metabolic response to dietary isoflavones in humans. Proc Soc Exp Biol Med 1995 ; 208 : 40-3. 50 Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991 ; 325 : 756-62. 51 Sirtori CR, Lovati MR, Manzoni C, Monetti M, Pazzucconi F, Gatti E. Soy and cholesterol reduction: Clinical experience. J Nutr 1995 ; 125 : 598S-605S. 52 Potter SM, Bakhit RM, Essex-Sorlie D, et al. Depression of plasma cholesterol in men by consumption of baked products containing soy protein. Am J Clin Nutr 1993 ; 58 : 501-6. 53 Anthony Clarkson MSTB, Williams JK. Effects of soy isoflavones on atherosclerosis: potential mechanisms. Am J Clin Nutr 1998 ; 68 : 1390S-3S. 54 Pan W, Ikeda K, Takebe M, Yamori Y. Genistein, daidzein and glycitein inhibit growth and DNA synthesis of aortic smooth muscle cells from stroke-prone spontaneously hypertensive rats. J Nutr 2001 ; 131 : 1154-8. 55 Kuruvilla A, Putcha G, Poulos E, Shearer WT. Tyrosine phosphorylation of phospholipase C concomitant with its activation by platelet-activating factor in a human B cell line. J Immunol 1993 ; 151 : 637-48. 56 Murphy CT, Kellie S, Westwick J. Tyrosine kinase activity in rabbit platelets stimulated with platelets-activating factor. The effect of inhibiting tyrosine kinase with genistein on plateletsignal-molecule elevation and functional responses. Eur J Biochem 1993 ; 216 : 639-51. 57 McNicol A. The effects of genistein on platelet function are due to thromboxane receptor antagonism rather than inhibition of tyrosine kinase. Prostaglandins Leukot Essent Fatty Acids 1993 ; 48 : 379-84. 58 Asahi M, Yanagi S, Ohta S, et al. Thrombin-induced human platelet aggregation is inhibited by protein tyrosine kinase inhibitors ST 638 and genistein. FEBS Lett 1992 ; 309 : 10-4.

43

59 Evans BAJ, Griffiths K, Morton MS. Inhibition of 5α-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol 1995 ; 147 : 295-302. 60 Makela S, Poutanen M, Lehtimaki J, Kostian ML, Santti R, Vihko R. Estrogen-specific 17ß-hydroxysteroid oxidoreductase type 1 (E. C. 1.1.1.62) as a possible target for the action of phytoestrogens. Proc Soc Exp Biol Med 1995 ; 208 : 51-9. 61 Joannou GE, Kelly GE, Reeder AY, Waring MA, Nelson C. A urinary profile study of dietary phytoestrogens: the identification and mode of metabolism of new isoflavonoids. J Steroid Biochem Mol Biol 1995 ; 54 : 167-84. 62 Kelly GE, Nelson C, Waring MA, Joannou GE, Reeder AY. Metabolites of dietary (soya) isoflavones in human urine. Clin Chim Acta 1993 ; 223 : 9-22. 63 Axelson M, Kirk DN, Cooley G, Farrant RD, Lawson AM, Setchell KDR. The identification of the weak estrogen equol (7-hydroxy-3-4’-hydroxyphenyl chroman) in human urine. Biochem J 1982 ; 201 : 353-7. 64 Slavin JL, Karr SC, Hutchins AM, Lampe JW. Influence of soybean processing, habitual diet and soy dose on urinary isoflavonoid excretion. Am J Clin Nutr. 1998 ; 68 : 1492S-5S. 65 Nagel SC, vom Saal FS, Welshons WV. The effective free fraction of estradiol and xenoestrogens in human serum measured by whole cell uptake assays: physiology of delivery modifies estrogenic activity. Proc Soc Exp Biol Med 1998 ; 217 : 300-9. 66 Setchell KDR, Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J Nutr 1999 ; 129 : 758S67S. 67 Lampe JW, Karr SC, Hutchins AM, Slavin JL. Urinary equol excretion with a soy challenge: influence of habitual diet. Proc Soc Exp Biol Med 1998 ; 217 : 335-9. 68 Mackenzie PI, Rodbourne L, Stranks S. Steroid UDP glucuronosyl-transferases. Steroid Biochem Mol Biol 1992 ; 43 : 1099-105. 69 Martucci CP, Fishman J. P450 enzymes of estrogen metabolism. Pharmacol Ther 1993 ; 57 : 237-57. 70 Morton MS, Wilcox G, Wahlqvist ML, Griffiths K. Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol 1994 ; 142 : 251-9. 71 Adlercreutz H, Fotsis T, Lampe J, Wahala K, Makela T, Brunow G, et al. Quantitative determination of lignans and isoflavones in plasma of omnivorous and vegetarian women by isotope-dilution gas chromatography-mass spectrometry. Scand J Clin Lab Investig 1993 ; 53 : 5-18. 72 Coward L, Kirk M, Albin N, Barnes S. Analysis of plasma isoflavones by reversed phase HPLC-multiple reaction ion monitoring mass spectrometry. Clin Chim Acta 1996 ; 247 : 121-42. 73 Barnes S, Grubbs C, Setchell KDR, Carlson J. Soybeans inhibit mammary tumors in model of breast cancer. In: Pariza M, Ed. Mutagens and carcinogens in the diet. City: Wiley-Liss, Inc.; 1990. p. 239-53. 74 Setchell KDR, Borriello SP, Hulme P, Kirk DN, Axelson M. Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. Am J Clin Nutr 1984 ; 40 : 56978. 75 Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest 1990 ; 201 (Suppl) : 3-23. 76 Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996 ; 17 : 271-5. 77 Zava DT, Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer 1997 ; 27 : 31-40.

44

H. Tapiero et al.

78 Ishida J, Nakagawa S, et al. Genistein a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987 ; 262 : 5592-6. 79 Peterson G, Barnes S. Genistein inhibition of the growth of human breast cancer cells–independence from estrogen receptors and multidrug resistance gene. Biochem Biophys Res Commun 1991 ; 179 : 661-7. 80 Setchell KDR. Non-steroidal estrogens of dietary origin: possible roles in health and disease, metabolism and physiological effects. Proc Nutr Soc N Z 1995 ; 20 : 1-21. 81 Adlercreutz H. Phytoestrogens: epidemiology and a possible role in cancer protection. Environ Health Perspect 1995 ; 103 : 103-11. 82 Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: emerging role of its effects through transforming growth factor beta signalling. Am J Clin Nutr 1998 ; 68 : 1418S-25S. 83 Traganos F, Ardelt B, Halko N, Bruno S, Darzynkiewicz Z. Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res 1992 ; 52 : 6200-8. 84 Matsukawa Y, Marui N, Sakai T, et al. Genistein arrests cell cycle progression at G2-M. Cancer Res 1993 ; 53 : 1328-31. 85 Pollard M, Luckert PH. Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr Cancer 1997 ; 28 : 41-5. 86 Massague J, Weis-Garcia F. Serine/threonine kinase receptors: mediators of transforming growth factor beta family signals. Cancer Surv 1996 ; 27 : 41-64. 87 Colletta AA, Benson JR, Baum M. Alternative mechanisms of action of anti-estrogens. Breast Cancer Res Treat 1994 ; 31 : 5-9. 88 Perry RR, Kang Y, Greaves BR. Relationship between tamoxifen-induced transforming growth factor Beta 1expression, cytostasis and apoptosis in human breast cancer cells. Br J Cancer 1995 ; 72 : 1441-6. 89 Butta A, MacLennan K, Flanders KC, et al. Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 1992 ; 52 : 4261-4. 90 Chen H, Tritton Tr, Kenny N, Absher M, Chiu JF. Tamoxifen induces TGF-beta 1activity and apoptosis of human MCF-7 breast cancer cells in vitro. J Cell Biochem 1996 ; 61 : 9-17. 91 Peterson TG, Barnes S, Kim H. Genistein may inhibit the growth of human mammary epithelial (HME) cells by augmenting transforming growth factor beta (TGFβ) signalling. Am J Clin Nutr 1998 ; 68 : 1527S-8S. 92 Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF beta. Nat Med 1996 ; 2 : 1132-6. 93 Anthony MS, Clarkson TB, Hughes CL, Morgan TM, Burke JL. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr 1996 ; 126 : 43-50. 94 Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991 ; 325 : 756-62. 95 Honore EK, Williams JK, Anthony MS, Clarckson TB. Soy isoflavones enhance coronary vascular reactivity in atherosclerotic female macaque. Ferti. Steril 1997 ; 67 : 148-54. 96 Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: emerging role of its effects via transforming growth factor β signalling pathways. Am J Clin Nutr 1998 ; 68 : 1418S-25S.

97 Li JD, Dohrman AF, Gallup M, et al. Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci U S A 1997 ; 94 : 967-72. 98 Novogrodsky A, Vanichkin A, Patya M, Gazit A, Osherov N, Levitzki A. Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors. Science 1994 ; 264 : 131922. 99 Okura A, Arakawa H, Oka H, Yoshinari T, Monden Y. Effect of genistein on topoisomerase activity and on the growth of [val12] Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Commun 1988 ; 157 : 183-9. 100 Markovits J, Linassier C, Fosse P, et al. Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 1989 ; 49 : 5111-7. 101 Yamamoto S, Shimizu K, Oonishi I, et al. Genistein suppresses cellular injury following hepatic ischemia/reperfusion. Transplant Proc 1996 ; 28 : 1111-5. 102 Bowen R, Cai Q, Rahn RO. Inhibition of UV light – and Fenton reaction-induced oxidative DNA damage by the soybean isoflavone genistein. Carcinogenesis 1996 ; 17 : 73-7. 103 Chait A. Effects of isoflavones on LDL-cholesterol in vitro but not in vivo [abstract]. Am J Clin Nutr 1998 ; 68 : 1523S. 104 Wang W, Franke A, Custer LJ, Marchand LL. Antioxidant properties of dietary phenolic agents in a human LDL oxidation ex vivo model [abstract]. Am J Clin Nutr 1998 ; 68 : 1523S. 105 Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R, Schweigerer L. Genistein a dietary ingested isoflavonoid inhibits cell proliferation and in vitro angiogenesis. J. Nutr 1995 ; 125 : 790S-7S. 106 Ogawara H, Akiyama T, Watanabe S-I, Ito N, Kobori M, Seoda Y. Inhibition of tyrosine protein kinase activity by synthetic isoflavones and flavones. J Antibiot (Tokyo) 1989 ; 42 : 340-3. 107 Peterson TG, Ji G-P, Kirk M, Coward L, Falany CN, Barnes S. Metabolism of the isoflavones genistein and Biochanin A in human breast cancer cell lines. Am J Clin Nutr 1998 ; 68 : 1505S-11S. 108 Kennedy AR. The evidence for soybean products as cancer preventive agents. J Nutr 1995 ; 125 : 733S-43S. 109 Kennedy AR. Chemopreventive agents: protease inhibitors. Pharmacol Ther 1998 ; 78 : 167-209. 110 Bowman DE. Differentiation of soybean antitryptic factors. Proc Soc Exp Med 1946 ; 63 : 547-50. 111 Birk Y. Purification and some properties of a highly active inhibitor of trypsin and chymotrypsin from soybeans. Biochim Biophys Acta 1961 ; 54 : 191-7. 112 Yavelow J, Collins M, Birk Y, Troll W, Kennedy AR. Nanomolar concentrations of Bowman-Birk soybean protease inhibitor suppress X-ray induced transformation in vitro. Proc Natl Acad Sci U S A 1985 ; 82 : 5395-9. 113 Goldstein BD, Witz G, Amoruso M, Troll W. Protease inhibitors antagonize the activation of polymorphonuclear leukocyte oxygen consumption. Biochem Biophys Res Commun 1997 ; 88 : 854-60. 114 Frenkel K, Chrzan K, Ryan CA, Wiesner R, Troll W. Chymotrypsin specific protease inhibitors decrease H2O2 formation by activated human polymorphonuclear leukocytes. Carcinogenesis 1987 ; 8 : 1207-12. 115 St Clair WH, St Clair DK, Kennedy AR. Comparison of the Bowman-Birk protease inhibitor to WR 1065 for protection against radiation induced DNA cellular and tissue damage. Cancer J 1991 ; 4 : 278-82.