Search tips
Search criteria 


Logo of genesnutspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
Genes Nutr. Sep 2006; 1(3-4): 161–176.
PMCID: PMC3454832
Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities
Paola Galluzzocorresponding author and Maria Marinocorresponding author
Department of Biology, University “Roma Tre”, Viale G. Marconi 446, I-00146 Roma, Italy
Maria Marino, Fax: +39-06-55176321, m.marino/at/
corresponding authorCorresponding author.
Received March 14, 2006; Accepted April 30, 2006.
Flavonoids are a large group of nonnutrient compounds naturally produced from plants as part of their defence mechanisms against stresses of different origins. They emerged from being considered an agricultural oddity only after it was observed that these compounds possess a potential protective function against several human degenerative diseases. This has led to recommending the consumption of food containing high concentrations of flavonoids, which at present, especially as soy isoflavones, are even available as overthecounter nutraceuticals. The increased use of flavonoids has occurred even though their mechanisms are not completely understood, in particular those involving the flavonoid impact on estrogen signals. In fact, most of the human health protective effects of flavonoids are described either as estrogenmimetic, or as antiestrogenic, while others do not involve estrogen signaling at all. Thus, the same molecule is reported as an endocrine disruptor, an estrogen mimetic or as an antioxidant without estrogenic effects. This is due in part to the complexity of the estrogen mechanism, which is conducted by different pathways and involves two different receptor isoforms. These pathways can be modulated by flavonoids and should be considered for a reliable evaluation of flavonoid, both estrogenicity and antiestrogenicity, and for a correct prediction of their effects on human health.
Full Text
The Full Text of this article is available as a PDF (383K).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
  • Acconcia F., Marino M. Synergism between genomic and non genomic estrogen action mechanisms. IUBMB Life. 2003;55:145–150. [PubMed]
  • Acconcia F., Ascenzi P., Bocedi A., Spisni E., Tomasi V., Trentalance A., Visca P., Marino M. Palmitoylationdependent estrogen receptor α membrane localization:regulation by 17β-estradiol. Molecular Biology of the Cell. 2005;16:231–237. doi: 10.1091/mbc.E04-07-0547. [PMC free article] [PubMed] [Cross Ref]
  • Acconcia F., Totta P., Ogawa S., Cardillo I., Inoue S., Leone S., Trentalance A., Muramatsu M., Marino M. Survival versus apoptotic 17β-estradiol effect: role of ERα and ERβ activated non-genomic signaling. Journal of Cellular Physiology. 2005;203:193–201. doi: 10.1002/jcp.20219. [PubMed] [Cross Ref]
  • Adachi T., Okuno Y., Takenaka S., Matsuda K., Ohta N., Takashima K., Yamazaki K., Nishimura D., Miyatake K., Mori C., Tsujimoto G. Comprehensive analysis of the effect of phytoestrogen, daidzein, on a testicular cell line, using mRNA and protein expression profile. Food and Chemical Toxicology. 2005;43:529–535. doi: 10.1016/j.fct.2004.12.006. [PubMed] [Cross Ref]
  • Ashby J., Odum J. Gene expression changes in the immature rat uterus: effects of uterotrophic and sub-uterotrophic doses of bisphenol a. Toxicological Sciences. 2004;82:458–467. doi: 10.1093/toxsci/kfh283. [PubMed] [Cross Ref]
  • Baker V.A., Hepburn P.A., Kennedy S.J., Jones P.A., Lea L.J., Sumpter J.P., Ashby J. Safety valuation of phytosterol esters. Part 1. Assessment of estrogenicity using a combination of in vivo and in vitro assays. Food and Chemical Toxicology. 1999;37:13–22. doi: 10.1016/S0278-6915(98)00101-X. [PubMed] [Cross Ref]
  • Barnes S. Soy Isoflavones-Phytoestrogens and What Else? The Journal of Nutrition. 2004;134:1225S–1228S. [PubMed]
  • Bayer T., Colnot T., Dekant W. Disposition and biotransformation of the estrogenic isoflavone daidzein in rats. Toxicology Science. 2001;62:205–211. doi: 10.1093/toxsci/62.2.205. [Cross Ref]
  • Belcher S. M., Zsarnovszky A. Estrogenic actions in the brain: estrogen, phytoestrogens, and rapid intracellular signaling mechanisms. The Journal of Pharmacology and Experimental Therapeutics. 2001;299:408–414. [PubMed]
  • Bennetts H. W., Underwood E. J., Shier F. L. A specific breeding problem of sheep on subterranean clover pasture in western Australia. Australian Veterinary Journal. 1946;22:2–12. [PubMed]
  • Birt D.F., Hendrich S., Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacology & Therapeutics. 2001;90:157–177. doi: 10.1016/S0163-7258(01)00137-1. [PubMed] [Cross Ref]
  • Bors W., Michel C., Stettmaier K. Antioxidant effects of flavonoids. Biofactors. 1997;6:399–402. [PubMed]
  • Bramlett K.S., Wu Y., Burris T. P. Ligands specify coactivator nuclear receptor (NR) box affinity for estrogen receptor subtypes. Molecular Endocrinology. 2001;15:909–922. doi: 10.1210/me.15.6.909. [PubMed] [Cross Ref]
  • Brownson D.M., Azios N.G., Fuqua B.K., Dharmawardhane S.F., Mabry T.J. Flavonoid effects relevant to cancer. The Journal of Nutrition. 2002;132:3482S–3489S. [PubMed]
  • Brzozowski A.M., Pike A.C., Dauter Z., Hubbard R.E., Bonn T., Engstrom O., Ohman L., Greene G.L., Gustafsson J.-Å., Carlquist M. Molecular basis of agonism and antagonism in the estrogen receptor. Nature. 1997;389:753–758. doi: 10.1038/39645. [PubMed] [Cross Ref]
  • Bunone G., Briand P.A., Miksicek R.J., Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. The EMBO Journal. 1996;15:2174–2183. [PubMed]
  • Cao G., Muccitelli H.U., Sanchez-Moreno C., Prior R.L. Anthocyanins are absorbed in glycated forms in elderly women: a pharmacokinetic study. The American Journal of Clinical Nutrition. 2001;73:920–926. [PubMed]
  • Cassidy A., Hanley B., Lamuela-Raventos R. M. Isoflavones, lignans, and stilbenes: Origins, metabolism, and potential importance to human health. Journal of the Science of Food Agriculture. 2000;80:1044–1062. doi: 10.1002/(SICI)1097-0010(20000515)80:7<1044::AID-JSFA586>3.0.CO;2-N. [Cross Ref]
  • Castagnetta L., Granata O.M., Cocciadiferro L., Saetta A., Polito L., Bronte G., Rizzo S., Campisi I., Agostana B., Carruba G. Sex steroids, carcinogenesis, and cancer progression. Annals of the New York Academy of Sciences. 2004;1028:233–246. doi: 10.1196/annals.1321.028. [PubMed] [Cross Ref]
  • Castoria G, Barone M.V., Domenico M., Bilancio A., Ametrano D., Migliaccio A., Auricchio E. Nontranscriptional action of oestradiol and progestin triggers DNA synthesis. The EMBO Journal. 1999;18:2500–2510. doi: 10.1093/emboj/18.9.2500. [PubMed] [Cross Ref]
  • Castoria G., Migliaccio A., Bilancio A., Domenico M., Falco A., Lombardi M., Fiorentino R., Varricchio L., Barone M.V., Auricchio F. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. The EMBO Journal. 2001;20:6050–6059. doi: 10.1093/emboj/20.21.6050. [PubMed] [Cross Ref]
  • Chambliss K.L., Yuhanna I.S., Anderson R.G., Mendelsohn M.E., Shaul P.W. ER? has nongenomic action in caveolae. Molecular Endocrinology. 2002;16:938–946. doi: 10.1210/me.16.5.938. [PubMed] [Cross Ref]
  • Cheung C. P., Yu S., Wong K. B., Chan L.W., Lai F. M. M., Wang X., Suetsugi M., Chen S., Chan F L. Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. The Journal of Clinical Endocrinology & Metabolism. 2005;90:1830–1844. doi: 10.1210/jc.2004-1421. [PubMed] [Cross Ref]
  • Cidlowski J. A. Nuclear receptor superfamily of proteins. 20 years after cloning. Molecular Endocrinology. 2005;19:1401–1666. doi: 10.1210/me.2005-0999. [Cross Ref]
  • Ciguère V. To ERR in the estrogen pathway. Trends in Endocrinology & Metabolism. 2002;13:220–225. doi: 10.1016/S1043-2760(02)00592-1. [PubMed] [Cross Ref]
  • Constantinou S., Kiguchi K., Huberman E. Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. Cancer Research. 1990;50:2618–2624. [PubMed]
  • Couteau D., McCartney A.L., Gibson G.R., Williamson G., Faulds C.B. Isolation and characterization of human colonic bacteria able to hydrolyse chlorogenic acid. Journal of Applied Microbiology. 2001;90:873–881. doi: 10.1046/j.1365-2672.2001.01316.x. [PubMed] [Cross Ref]
  • Coward L., Barnes N.C., Setchell K.D.R., Barnes S. Genistein, daidzein, and their beta-glycoside conjugates: antitumor isoflavones in soybean foods from American and Asian diets. Journal of Agricultural and Food Chemistry. 1993;41:1961–1967. doi: 10.1021/jf00035a027. [Cross Ref]
  • Dan P., Cheung J.C., Scriven D.R., Moore E.D. Epitope-dependent localization of estrogen receptor-α, but not - β, in en face arterial endothelium. American Journal of Physiology. Heart and Circulatory Physiology. 2003;284:H1295–H1306. [PubMed]
  • Dang Z.C., Lowik C. Dose-dependent effects of phytoestrogens on bone. Trends in Endocrinology and Metabolism. 2005;16:207–213. doi: 10.1016/j.tem.2005.05.001. [PubMed] [Cross Ref]
  • Davis S. R., Murkies A. L., Wilcox G. Phytoestrogens in clinical practice. Integrative Medicine. 1998;1:27–34. doi: 10.1016/S1096-2190(98)00019-5. [Cross Ref]
  • Kleijn M.J., Schouw Y.T., Wilson P.W., Adlercreutz H., Mazur W., Grobbee D.E., Jacques RE. Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study. The Journal of Nutrition. 2001;131:1826–1832. [PubMed]
  • Delclos K.B., Bucci T.J., Lomax L.G., Latendresse J.R., Warbritton A., Weis C.C., Newbold R.R. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reproductive Toxicology. 2001;15:647–663. doi: 10.1016/S0890-6238(01)00177-0. [PubMed] [Cross Ref]
  • Distefano E., Marino M., Gillette J.A., Hanstein B., Pallottini V., Bruning J., Krone W., Trentalance A. Role of tyrosine kinase signaling in estrogen-induced LDL receptor gene expression in HepG2 cells. Biochimica et Biophysica Acta. 2002;1580:145–149. [PubMed]
  • Dixon R.A. Phytoestrogens. Annual Review of Plant Biology. 2004;55:225–261. doi: 10.1146/annurev.arplant.55.031903.141729. [PubMed] [Cross Ref]
  • Doerge D.R., Twaddle N.C., Churchwell M.I., Newbold R.R., Delclos K.B. Lactational transfer of the soy isoflavone, genistein, in Sprague-Dawley rats consuming dietary genistein. Reproductive Toxicology. 2006;21:307–312. doi: 10.1016/j.reprotox.2005.09.007. [PubMed] [Cross Ref]
  • Enmark E., Pelto-Huikko M., Grandinen K., Lagercrantz S., Lagercrantz J., Fried G., Nordenskjold M., Gustafsson J-Å. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. The Journal of Clinical Endocrinology and Metabolism. 1997;82:4258–4265. doi: 10.1210/jc.82.12.4258. [PubMed] [Cross Ref]
  • Escande A., Pillon A., Servant N., Cravedi J.P., Larrea F., Muhn P., Nicolas J.C., Cavailles V., Balaguer P. Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor α or β Biochemical Pharmacology. 2006;71:1459–1469. doi: 10.1016/j.bcp.2006.02.002. [PubMed] [Cross Ref]
  • Farach-Carson M.C., Davis P.J. Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways. The Journal of Pharmacology and Experimental Therapeutics. 2003;307:839–845. doi: 10.1124/jpet.103.055038. [PubMed] [Cross Ref]
  • Fitzpatrick L.A. Alternatives to estrogen. The Medical Clinics of North America. 2003;87:1091–1113. doi: 10.1016/S0025-7125(03)00116-0. [PubMed] [Cross Ref]
  • Flynn K.M., Ferguson S.A., Delclos K.B., Newbold R.R. Effects of genistein exposure on sexually dimorphic behaviors in rats. Toxicology Science. 2000;55:311–319. doi: 10.1093/toxsci/55.2.311. [Cross Ref]
  • Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proceedings of the National Academy of Sciences of the United States of America. 1993;90:2690–2694. doi: 10.1073/pnas.90.7.2690. [PubMed] [Cross Ref]
  • Gamet-Payrastre L., Manenti S., Gratacap M.P., Tulliez J., Chap H., Payrastre B. Flavonoids and the inhibition of PKC and PI3-kinase. General Pharmacology. 1999;32:279–286. doi: 10.1016/S0306-3623(98)00220-1. [PubMed] [Cross Ref]
  • Garrels J.I. The QUEST system for quantitative analysis of two-dimensional gels. Journal of Biological Chemistry. 1989;264:5269–5282. [PubMed]
  • Glass C.K., Rosenfeld M.G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes & Development. 2000;14:121–141. [PubMed]
  • Gonthier M.P., Verny M.A., Besson C., Rémésy C., Scalbert A. Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. The Journal of Nutrition. 2003;133:1853–1859. [PubMed]
  • Graefe E.U., Wittig J., Mueller S., Riethling A.K., Uehleke B., Drewelow B., Pforte H., Jacobasch G., Derendorf H., Veit M. Pharmacokinetics and bioavailability of quercetin glycosides in humans. Journal of Clinical Pharmacology. 2001;41:492–499. doi: 10.1177/00912700122010366. [PubMed] [Cross Ref]
  • Green S., Walter P., Kumar V., Krust A., Bornert J.M., Argos P., Chambon P. Human estrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986;320:134–139. doi: 10.1038/320134a0. [PubMed] [Cross Ref]
  • Guo T.L., Germolec D.R., Musgrove D.L., Delclos K.B., Newbold R.R., Weis C.C., White K.L. Myelotoxicity in genistein-, nonylphenol-, methoxychlor-, vinclozolinor ethinyl estradiol-exposed F1 generations of Sprague-Dawley rats following developmental and adult exposures. Toxicology. 2005;211:207–219. doi: 10.1016/j.tox.2005.03.008. [PubMed] [Cross Ref]
  • Heinonen M. Anthocyanins as dietary antioxidants. In: Voutilainen S, Salonen J.T., editors. Third international conference on natural antioxidants and anticarcinogens in food, health, and disease (NAHD) Helsinki, Finland. Helsinki: Kuopion Yliopisto; 2001. pp. 25–25.
  • Hendrich S., Wang G. J., Lin H. K., Xu X., Tew B. Y., Wang H. J., Murphy P. A. Isoflavones metabolism and bioavailability. In: Pappas A., editor. Antioxidant Status, Diet, Nutrition and Health. Boca Raton: CRC Press LLC; 1998. pp. 211–230.
  • Hertog M.G, Feskens E.J., Kromhout D. Antioxidant flavonols and coronary heart disease risk. Lancet. 1997;349:699–699. doi: 10.1016/S0140-6736(05)60135-3. [PubMed] [Cross Ref]
  • Hertog M.G.L., Hollman P.C.H., Katan M.B., Kromhout D. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in the Netherlands. Nutrition and Cancer. 1993;20:21–29. doi: 10.1080/01635589309514267. [PubMed] [Cross Ref]
  • Heruth D. P., Wetmore L. A., Leyva A., Rothberg P. G. Influence of protein tyrosine phosphorylation on the expression of the c-myc oncogene in cancer of the large bowel. Journal of Cellular Biochemistry. 1995;58:83–94. doi: 10.1002/jcb.240580111. [PubMed] [Cross Ref]
  • Herynk M.H., Fuqua S.A. Estrogen receptor mutations in human disease. Endocrine Reviews. 2004;25:869–898. doi: 10.1210/er.2003-0010. [PubMed] [Cross Ref]
  • Hirata S., Shoda T., Kato J., Hoshi K. Isoform/ variant mRNAs for sex steroid hormone receptors in humans. Trends in Endocrinology and Metabolism. 2003;14:124–129. doi: 10.1016/S1043-2760(03)00028-6. [PubMed] [Cross Ref]
  • Hollman P.C.H., Katan M.B. Dietary flavonoids: intake, health effects and bioavailability. Food and Chemical Toxicology. 1999;37:937–942. doi: 10.1016/S0278-6915(99)00079-4. [PubMed] [Cross Ref]
  • Hollman P.C.H., Hertog M.G., Katan M.B. Role of dietary flavonoids in protection against cancer and coronary heart disease. Biochemical Society Transactions. 1996;24:785–789. [PubMed]
  • Hollman P.C.H., Trijp J.M.P., Buysman M.N.C.P., Gaag M.S., Mengelers M.J., Vries J.H., Katan M.B. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Letters. 1997;418:152–156. doi: 10.1016/S0014-5793(97)01367-7. [PubMed] [Cross Ref]
  • Inoue A., Yoshida N., Omoto Y, Oguchi S., Yamori T., Kiyama R., Hayashi S. Development of cDNA microarray for expression profiling of estrogen-responsive genes. Journal of Molecular Endocrinology. 2002;29:175–192. doi: 10.1677/jme.0.0290175. [PubMed] [Cross Ref]
  • Jacobs M.N., Lewis D.F. Steroid hormone receptors and dietary ligands: a selected review. Proceedings of the Nutrition Society. 2002;61:105–122. [PubMed]
  • Jordan V.C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1. Receptor interactions. Journal of Medicinal Chemistry. 2003;46:883–908. doi: 10.1021/jm020449y. [PubMed] [Cross Ref]
  • Justesen U., Knuthsen P., Leth T. Determination of plant polyphenols in Danish foodstuffs by HPLC-UV and LC-MS detection. Cancer Letters. 1997;114:165–167. doi: 10.1016/S0304-3835(97)04651-X. [PubMed] [Cross Ref]
  • Keinan-Boker L., Schouw Y.T., Grobbee D.E., Peeters P.H. Dietary phytoestrogens and breast cancer risk. The American Journal of Clinical Nutrition. 2004;79:282–288. [PubMed]
  • Kelly G. E., Nelson C., Waring M. A., Joannou G. E., Reeder A. Y. Metabolites of dietary (soya) isoflavones in human urine. Clinica ChimicaActa. 1993;223:9–22. doi: 10.1016/0009-8981(93)90058-C. [Cross Ref]
  • King R. A., Bursill D. B. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. The American Journal of Clinical Nutrition. 1998;67:867–872. [PubMed]
  • Kirk E.A., Sutherland P., Wang S.A., Chait A., LeBoeuf R.C. Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor-deficient mice. The Journal of Nutrition. 1998;128:954–959. [PubMed]
  • Klinge C.M., Blankenship K.A., Risinger K.E., Bhatnagar S., Noisin E.L., Sumanasekera W.K., Zhao L., Brey D.M., Keynton R.S. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. The Journal of Biological Chemistry. 2005;280:7460–7468. doi: 10.1074/jbc.M411565200. [PubMed] [Cross Ref]
  • Kousteni S., Chen J.R., Bellido T., Han L., Ali A.A., O’Brien C.A., Plotkin L., Fu Q., Mancino A.T., Wen Y., Vertino A.M., Powers C.C., Stewart S.A., Ebert R., Parfitt A.M., Weinstein R.S., Jilka R.L., Manolagas S.C. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science. 2002;298:843–846. doi: 10.1126/science.1074935. [PubMed] [Cross Ref]
  • Kraus W.L., Wong J. Nuclear receptor-dependent transcription with chromatin. Is it all about enzymes? European Journal of Biochemistry. 2002;269:2275–2283. doi: 10.1046/j.1432-1033.2002.02889.x. [PubMed] [Cross Ref]
  • Kris-Etherton P.M., Hecker K.D., Bonanome A., Coval S.M., Binkoski A.E., Hilpert K.F., Griel A.E., Etherton T.D. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. The American Journal of Medicine. 2002;113(9B):71S–88S. doi: 10.1016/S0002-9343(01)00995-0. [PubMed] [Cross Ref]
  • Kuhnau J. The flavonoids. A class of semi-essential food components: their role in human nutrition. World Review of Nutrition and Dietetics. 1976;24:117–191. [PubMed]
  • Kuiper G.G.J.M., Enmark E., Pelto-Huikko M., Nilsson S., Gustafsson J.-Å. Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences of the United States of America. 1996;93:5925–5930. doi: 10.1073/pnas.93.12.5925. [PubMed] [Cross Ref]
  • Kuiper G.G.J.M., Lemmen J.G., Carlsson B., Corton J.C., Safe S.H., Saag P.T., Burg B., Gustafsson J.-Å. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β Endocrinology. 1998;139:4252–4263. doi: 10.1210/en.139.10.4252. [PubMed] [Cross Ref]
  • Kumar V., Green S., Stack G., Berry M., Jin J.R., Chambon P. Functional domains of the human estrogen receptor. Cell. 1987;51:941–951. doi: 10.1016/0092-8674(87)90581-2. [PubMed] [Cross Ref]
  • Kumpulainen J.T. Intake of flavonoids, phenolic acids and lignans in various populations. In: Voutilainen S., Salonen J.T., editors. Third international conference on natural antioxidants and anticarcinogens in food, health, and disease (NAHD) Helsinki: Kuopion Yliopisto; 2001. pp. 24–24.
  • Kuo M.-L., Lin J.-K., Huang T.-S., Yang N.-C. Reversion of the transformed phenotypes of v-H-ras NIH3T3 cells by flavonoids through attenuating the content of phosphotyrosine. Cancer Letters. 1994;87:91–97. doi: 10.1016/0304-3835(94)90414-6. [PubMed] [Cross Ref]
  • Leers J., Treuter E., Gustafsson J.-Å. Mechanistic principles in NR box-dependent interaction between nuclear hormone receptors and the coactivator TIF2. Molecular and Cellular Biology. 1998;18:6001–6013. [PMC free article] [PubMed]
  • Lehmann L., Esch H.L., Wagner J., Rohnstock L., Metzler M. Estrogenic and genotoxic potential of equol and two hydroxylated metabolites of daidzein in cultured human Ishikawa cells. Toxicology Letters. 2005;158:72–86. doi: 10.1016/j.toxlet.2005.02.011. [PubMed] [Cross Ref]
  • Levin E.R. Integration of the extranuclear and nuclear actions of estrogen. Molecular Endocrinology. 2005;19:1951–1959. doi: 10.1210/me.2004-0390. [PMC free article] [PubMed] [Cross Ref]
  • Limer J.L., Speirs V. Phyto-oestrogens and breast cancer chemoprevention. Breast Cancer Research. 2004;6:119–127. doi: 10.1186/bcr781. [PMC free article] [PubMed] [Cross Ref]
  • Liu M. M., Albanese C., Anderson C. M., Hilty K., Webb P., Uht R. M., Price R. H., Pestell R. G., Kushner P. J. Opposing action of estrogen receptors α and β on cyclin D1 gene expression. The Journal of Biological Chemistry. 2002;277:24353–24360. doi: 10.1074/jbc.M201829200. [PubMed] [Cross Ref]
  • Lobenhofer E.K., Huper G., Iglehart J.D., Marks J.R. Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF-7 cells prevents estrogen-induced mitogenesis. Cell Growth and Differentiation. 2000;11:99–110. [PubMed]
  • Losel R.M., Falkenstein E., Feuring M., Schultz A., Tillmann H.C., Rossol-Haseroth K., Wehling M. Nongenomic steroid action: controversies, questions, and answers. Physiological Reviews. 2003;83:965–1016. [PubMed]
  • Lu L. J., Lin S. N., Grady J. J., Nagamani M., Anderson K. E. Altered kinetics and extent of urinary daidzein and genistein excretion in women during chronic soya exposure. Nutrition and Cancer. 1997;26:289–302. doi: 10.1080/01635589609514485. [PubMed] [Cross Ref]
  • Maggi A., Ciana P. Reporter mice and drug discovery and development. Nature Reviews. Drug Discovery. 2005;4:249–255. doi: 10.1038/nrd1661. [PubMed] [Cross Ref]
  • Maggi A., Ottobrini L., Biserni A., Lucignani G., Ciana P. Reporter mice: a new way to look at drug action. Trends in Pharmacological Science. 2004;25:337–342. doi: 10.1016/ [Cross Ref]
  • Maggiolini M., Vivacqua A., Fasanella G., Recchia A.G., Sisci D., Pezzi V., Montanaro D., Musti A.M., Picard D., Andò S. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17β-estradiol and phytoestrogens in breast cancer cells. The Journal of Biological Chemistry. 2004;279:27008–27016. doi: 10.1074/jbc.M403588200. [PubMed] [Cross Ref]
  • Manach C., Scalbert A., Morand C., Remesy C., Jimenez L. Polyphenols: food sources and bioavailability. American Journal of Clinical Nutrition. 2004;79:727–747. [PubMed]
  • Manas E.S., Xu Z.B., Unwalla R.J., Somers W.S. Understanding the selectivity of genistein for human estrogen receptor-β using X-ray crystallography and computational methods. Structure. 2004;12:2197–2207. doi: 10.1016/j.str.2004.09.015. [PubMed] [Cross Ref]
  • Manavathi B., Kumar R. Steering estrogen signals from the plasma membrane to the nucleus: Two sides of the coin. Journal of Cellular Physiology. 2005;207:594–604. doi: 10.1002/jcp.20551. [PubMed] [Cross Ref]
  • Manolagas S.C., Kousteni S., Jilka R.L. Sex steroids and bone. Recent Progress in Hormone Research. 2002;57:385–409. doi: 10.1210/rp.57.1.385. [PubMed] [Cross Ref]
  • Marino M., Acconcia F., Ascenzi P. Estrogen receptor signalling: bases for drug actions. Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 2005;5:305–314. doi: 10.2174/1568008054863763. [PubMed] [Cross Ref]
  • Marino M., Acconcia F., Trentalance A. Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Molecular Biology of the Cell. 2003;14:2583–2591. doi: 10.1091/mbc.E02-09-0621. [PMC free article] [PubMed] [Cross Ref]
  • Marino M., Acconcia F., Bresciani F., Weisz A., Trentalance A. Distinct nongenomic signal transduction pathways controlled by 17β-estradiol regulate DNA synthesis and cyclin D1 gene transcription in HepG2 cells. Molecular Biology of the Cell. 2002;13:3720–3729. doi: 10.1091/mbc.E02-03-0153. [PMC free article] [PubMed] [Cross Ref]
  • Marino M., Distefano E., Pallottini V., Caporali S., Ceracchi G., Trentalance A. beta-estradiol stimulation of DNA synthesis requires different PKC isoforms in HepG2 and MCF7 cells. Journal of Cellular Physiology. 2001;188:170–177. doi: 10.1002/jcp.1105. [PubMed] [Cross Ref]
  • Marino M., Pallottini V., Trentalance A. Estrogens cause rapid activation of IP3-PKC-α signal transduction pathway in HEPG2 cells. Biochemical and Biophysical Research Communications. 1998;245:254–258. doi: 10.1006/bbrc.1998.8413. [PubMed] [Cross Ref]
  • Martin M.E., Haourigui M., Pelissero C., Benassayag C., Nunez E.A. Interactions between phytoestrogens and human sex steroid binding protein. Life Science. 1996;58:429–436. doi: 10.1016/0024-3205(95)02308-9. [Cross Ref]
  • Maruyama S., Fujimoto N., Asano K., Ito A. Suppression by estrogen receptor β of AP-1 mediated transactivation through estrogen receptor α The journal of steroid biochemistry and molecular biology. 2001;78:177–184. doi: 10.1016/S0960-0760(01)00083-8. [PubMed] [Cross Ref]
  • Matthews J., Gustafsson J.-Å. Estrogen signaling: a subtle balance between ERα and ERβ Molecular Interventions. 2003;3:281–292. doi: 10.1124/mi.3.5.281. [PubMed] [Cross Ref]
  • McDonnell D.P. Mining the complexities of the estrogen signaling pathways for novel therapeutics. Endocrinology. 2003;144:4237–4240. doi: 10.1210/en.2003-0900. [PubMed] [Cross Ref]
  • McDonnell D.P., Clemm D.L., Hermann T., Goldman M.E., Pike J.W. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Molecular Endocrinology. 1995;9:659–669. doi: 10.1210/me.9.6.659. [PubMed] [Cross Ref]
  • McKenna N.J., O’Malley B.W. An issue of tissues: divining the split personalities of selective estrogen receptor modulators. Nature Medicine. 2000;6:960–962. doi: 10.1038/79637. [PubMed] [Cross Ref]
  • Middleton E., Kandaswami C., Theoharides T.C. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacological Reviews. 2000;52:673–751. [PubMed]
  • Mikkola T.S., Clarkson T.B. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovascular Research. 2002;53:605–619. doi: 10.1016/S0008-6363(01)00466-7. [PubMed] [Cross Ref]
  • Monroe D.G., Secreto F.J., Subramaniam M., Getz B.J., Khosla S., Spelsberg T.C. Estrogen receptor α and β heterodimers exert unique effects on estrogen- and tamoxifen-dependent gene expression in human U2OS osteosarcoma cells. Molecular Endocrinology. 2005;19:1555–1568. doi: 10.1210/me.2004-0381. [PubMed] [Cross Ref]
  • Mosselman S., Polman J., Dijkema R. ERβ: identification and characterization of a novel human estrogen receptor. FEBS Letters. 1996;392:49–53. doi: 10.1016/0014-5793(96)00782-X. [PubMed] [Cross Ref]
  • Mueller S. O. Overview of in vitro tools to assess the estrogenic and antiestrogenic activity of phytoestrogens. Journal of Chromatography. 2002;B777:155–165. [PubMed]
  • Mueller S. O., Simon S., Chae K., Metzler M., Korach K. S. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor α (ERα) and ERβ in human cells. Toxicological Science. 2004;80:14–25. doi: 10.1093/toxsci/kfh147. [Cross Ref]
  • Naciff J. M., Jump M. L., Torontali S. M., Carr G. J., Tiesman J. P., Overmann G. J., Daston G. P. Gene expression profile induced by 17α-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Toxicological Science. 2002;68:184–199. doi: 10.1093/toxsci/68.1.184. [Cross Ref]
  • Naciff J. M., Overmann G. J., Torontali S. M., Carr G. J., Tiesman J. P., Daston G. P. Impact of the phytoestrogen content of laboratory animal feed on the geneexpression profile of the reproductive system in the immature female rat. Environmental Health Perspectives. 2004;112:1519–1526. doi: 10.1289/ehp.6848. [PMC free article] [PubMed] [Cross Ref]
  • Nilsson S., Makela S., Treuter E., Tujague M., Thomsen J., Andersson G., Enmark E., Pettersson K., Warner M., Gustafsson J.-Å. Mechanisms of estrogen action. Physiological Reviews. 2001;81:1535–1565. [PubMed]
  • Norman A. W., Mizwicki M. T., Norman D. P. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nature Reviews. Drug Discovery. 2004;3:27–41. doi: 10.1038/nrd1283. [PubMed] [Cross Ref]
  • The validation of test methods considered for adoption as OECD test guidelines. Paris: OECD; 1998.
  • Ogawa S., Inoue S., Watanabe T., Hiroi H., Orimo A., Hosoi T., Ouchi Y., Muramatsu M. The complete primary structure of human estrogen receptor β (hERβ) and its heterodimerization with ERα in vivo and in vitro. Biochemical and Biophysic Research Communications. 1998;243:122–126. doi: 10.1006/bbrc.1997.7893. [Cross Ref]
  • Oh H.Y., Kim S.S., Chung H.Y., Yoon S. Isoflavone supplements exert hormonal and antioxidant effects in postmenopausal Korean women with diabetic retinopathy. Journal of Medicinal Food. 2005;8:1–7. doi: 10.1089/jmf.2005.8.1. [PubMed] [Cross Ref]
  • Owens W., Ashby J., Odum J., Onyon L. The OECD program to validate the rat uterotrophic bioassay. Phase 2: dietary phytoestrogen analyses. Environmental Health Perspectives. 2003;111:1559–1567. doi: 10.1289/ehp.5949. [PMC free article] [PubMed] [Cross Ref]
  • Paech K., Webb P., Kuiper G.G.J.M., Nilsson S., Gustafsson J.-Å., Kushner P.J., Scanlan T.S. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science. 1997;277:1508–1510. doi: 10.1126/science.277.5331.1508. [PubMed] [Cross Ref]
  • Pedram A., Razandi M., Aitkenhead M., Hughes C.C., Levin E.R. Integration of the non-genomic and genomic actions of estrogen. Membrane-initiated signaling by steroid to transcription and cell biology. The Journal of Biological Chemistry. 2002;277:50768–50775. doi: 10.1074/jbc.M210106200. [PubMed] [Cross Ref]
  • Pennisi E. A low number wins the GeneSweep pool. Science. 2003;300:1484–1484. doi: 10.1126/science.300.5625.1484b. [PubMed] [Cross Ref]
  • Peters G.A., Khan S.A. Estrogen receptor domains E and F: role in dimerization and interaction with coactivator RIP-140. Molecular Endocrinology. 1999;13:286–296. doi: 10.1210/me.13.2.286. [PubMed] [Cross Ref]
  • Pietta P.G. Flavonoids as antioxidants. Journal of Natural Products. 2000;63:1035–1042. doi: 10.1021/np9904509. [PubMed] [Cross Ref]
  • Rachez C., Freedman L.P. Mediator complexes and transcription. Current Opinion in Cell Biology. 2001;13:274–280. doi: 10.1016/S0955-0674(00)00209-X. [PubMed] [Cross Ref]
  • Ramanathan L., Gray W.G. Identification and characterization of a phytoestrogen-specific gene from the MCF-7 human breast cancer cell. Toxicology and Applied Pharmacology. 2003;191:107–117. doi: 10.1016/S0041-008X(03)00221-7. [PubMed] [Cross Ref]
  • Ricketts M.-L., Moore D.D., Banz W.J., Mezei O., Shay N.F. Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors. A review. Journal of Nutritional Biochemistry. 2005;16:321–330. doi: 10.1016/j.jnutbio.2004.11.008. [PubMed] [Cross Ref]
  • Rimbach G., Pascual T.-S., Ewins B.A., Matsugo S., Uchida Y., Minihane A.M., Turner R., Vafei A.K., Weinberg P.D. Antioxidant and free radical scavenging activity of isoflavone metabolites. Xenobiotica. 2003;33:913–25. doi: 10.1080/0049825031000150444. [PubMed] [Cross Ref]
  • Routledge E.J., White R., Parker M.G., Sumpter J.P. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) α and ERβ? The Journal of Biological Chemistry. 2000;275:35986–35993. doi: 10.1074/jbc.M006777200. [PubMed] [Cross Ref]
  • Ruehlmann D.O., Steinert J.R., Valverde M.A., Jacob R., Mann G.E. Environmental estrogenic pollutants induce acute vascular relaxation by inhibiting L-type Ca2+ channels in smooth muscle cells. The FASEB Journal. 1998;12:613–619. [PubMed]
  • Sampson L., Rimm E., Hollman P.C., Vries J.H., Katan M.B. Flavonol and flavone intakes in US health professionals. Journal of the American Dietetic Association. 2002;102:1414–1420. doi: 10.1016/S0002-8223(02)90314-7. [PubMed] [Cross Ref]
  • Scalbert A., Williamson G. Dietary intake and bioavailability of polyphenols. The Journal of Nutrition. 2000;130:2073S–2085S. [PubMed]
  • Schaefer O., Humpel M., Fritzemeier K.H., Bohlmann R., Schleuning W.D. 8-Prenylnaringenin is a potent ER? selective phytoestrogen present in hops and beer. Journal of Steroid Biochemistry and Molecular Biology. 2003;84:359–360. doi: 10.1016/S0960-0760(03)00050-5. [PubMed] [Cross Ref]
  • Selvaraj V., Zakroczymski M.A., Naaz A., Mukai M., Ju Y.H., Doerge D.R., Katzenellenbogen J.A., Helferich W.G., Cooke P.S. Estrogenicity of the isoflavone metabolite equol on reproductive and non-reproductive organs in mice. Biology of Reproduction. 2004;71:966–972. doi: 10.1095/biolreprod.104.029512. [PubMed] [Cross Ref]
  • Setchell K.D., Brown N.M., Lydeking-Olsen E. The clinical importance of the metabolite equol-A clue to the effectiveness of soy and its isoflavones. The Journal of Nutrition. 2002;132:3577–3584. [PubMed]
  • Shay N.F., Banz W.J. Regulation of gene transcription by botanicals: novel regulatory mechanisms. Annual Review of Nutrition. 2005;25:297–315. doi: 10.1146/annurev.nutr.25.050304.092639. [PubMed] [Cross Ref]
  • Shutt D. A., Cox R. I. Steroid and phyto-estrogen binding to sheep uterine receptors in vitro. The Journal of Endocrinology. 1972;52:299–310. [PubMed]
  • Simoncini T., Hafezi-Moghadam A., Brazil D.P., Ley K., Chin W.W., Liso J.K. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000;407:538–451. doi: 10.1038/35035131. [PMC free article] [PubMed] [Cross Ref]
  • Smith C.L., O’Malley B.W. Coregulator function: a key to understanding tissue specificity of elective receptor modulators. Endocrine Reviews. 2004;25:45–71. doi: 10.1210/er.2003-0023. [PubMed] [Cross Ref]
  • Song R.X., Zhang Z., Santen R.J. Estrogen rapid action via protein complex formation involving ERα and Src. Trends in Endocrinology and Metababolism. 2005;16:347–353. doi: 10.1016/j.tem.2005.06.010. [Cross Ref]
  • Spencer J.P., Schroeter H., Crossthwaithe A.J., Kuhnle G., Williams R.J., Rice-Evans C. Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radical Biology & Medicine. 2001;31:1139–1146. doi: 10.1016/S0891-5849(01)00704-3. [PubMed] [Cross Ref]
  • Stevens J.F., Page J. E. Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry. 2004;65:1317–1330. doi: 10.1016/j.phytochem.2004.04.025. [PubMed] [Cross Ref]
  • Suetsugi M., Su L., Karlsberg K., Yuan Y.C., Chen S. Flavone and isoflavone phytoestrogens are agonists of estrogenrelated receptors. Molecular Cancer Research. 2003;1:981–991. [PubMed]
  • Szego C. M., Davis J. S. Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proceedings of the National Academy of Sciences of the United States of America. 1967;58:1711–1718. doi: 10.1073/pnas.58.4.1711. [PubMed] [Cross Ref]
  • Terasaka S., Aita Y., Inoue A., Hayashi S., Nishigaki M., Aoyagi K., Sasaki H., Wada-Kiyama Y., Sakuma Y., Akaba S., Tanaka J., Sone H., Yonemoto J., Tanji M., Kiyama R. Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals. Environmental Health Perspectives. 2004;112:773–781. [PMC free article] [PubMed]
  • Totta P., Acconcia F., Leone S., Cardillo I., Marino M. Mechanisms of naringenin-induced apoptotic cascade in cancer cells: involvement of estrogen receptor α and β signalling. IUBMB Life. 2004;56:491–499. doi: 10.1080/15216540400010792. [PubMed] [Cross Ref]
  • Totta P., Acconcia F., Virgili F., Cassidy A., Weinberg P.D., Rimbach G., Marino M. Daidzein-sulfate metabolites affect transcriptional and antiproliferative activities of estrogen receptor-? in cultured human cancer cells. The Journal of Nutrition. 2005;135:2687–2693. [PubMed]
  • Tremblay G.B., Tremblay A., Labrie F., Giguere V. Dominant activity of activation function 1 (AF-1) and differential stoichiometric requirements for AF-1 and -2 in the estrogen receptor alpha-beta heterodimeric complex. Molecular and Cellular Biology. 1999;19:1919–1927. [PMC free article] [PubMed]
  • Turner R., Baron T., Wolffram S., Minihane A.M., Cassidy A., Rimbach G., Weinberg P.D. Effect of circulating forms of soy isoflavones on the oxidation of low density lipoprotein. Free Radical Research. 2004;38:209–216. doi: 10.1080/10715760310001641854. [PubMed] [Cross Ref]
  • Erp-Baart M.A., Brants H.A., Kiely M., Mulligan A., Turrini A., Sermoneta C., Kilkkinen A., Valsta L.M. Isoflavone intake in four different European countries: the VENUS approach. British Journal of Nutrition. 2003;89:S25–S30. doi: 10.1079/BJN2002793. [PubMed] [Cross Ref]
  • Virgili F., Acconcia F., Ambra R., Rinna A., Totta P., Marino M. Nutritional flavonoids modulate estrogen receptor α signaling. IUBMB Life. 2004;56:145–151. [PubMed]
  • Weigel N.L., Zhang Y. Ligand-independent activation of steroid hormone receptors. Journal of Molecular Medicine. 1998;76:469–479. doi: 10.1007/s001090050241. [PubMed] [Cross Ref]
  • Weihua Z., Andersson S., Cheng G., Simpson E.R., Warner M., Gustafsson J.-Å. Update on estrogen signaling. FEBS Letters. 2003;46:17–24. doi: 10.1016/S0014-5793(03)00436-8. [PubMed] [Cross Ref]
  • Wijayaratne A.L., Nagel S.C., Paige L.A., Christensen D.J., Norris J.D., Fowlkes D.M., McDonnell D.P. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology. 1999;140:5828–5840. doi: 10.1210/en.140.12.5828. [PubMed] [Cross Ref]
  • Wrenn C.K., Katzenellenbogen B.S. Structure-function analysis of the hormone binding domain of the human estrogen receptor by region-specific mutagenesis and phenotypic screening in yeast. The Journal of Biological Chemistry. 1993;268:24089–24098. [PubMed]
  • Xu X., Harris K. S., Wang H.-J., Murphy P. A., Hendrich S. Bioavailability of soybean isoflavones depends upon gut microflora in women. The Journal of Nutrition. 1995;125:2307–2315. [PubMed]
  • Xu X., Wang H.-J., Murphy P. A., Cook L., Hendrich S. Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. The Journal of Nutrition. 1994;124:825–832. [PubMed]
  • Yager J.D., Davidson N.E. Estrogen carcinogenesis in breast cancer. The New England Journal of Medicine. 2006;354:270–282. doi: 10.1056/NEJMra050776. [PubMed] [Cross Ref]
  • Zhang Q.X., Hilsenbeck S.G., Fuqua S.A., Borg A. Multiple splicing variants of the estrogen receptor are present in individual human breast tumors. Journal of Steroid and Biochemical Molecular Biology. 1996;59:251–260. doi: 10.1016/S0960-0760(96)00120-3. [Cross Ref]
  • Zhang Y., Wang G.J., Song T.T., Murphy P.A., Hendrich S. Urinary disposition of the soybean isoflavones daidzein, genistein and glycitein differs among humans with moderate fecal isoflavone degradation activity. The Journal of Nutrition. 1999;129:957–962. [PubMed]
Articles from Genes & Nutrition are provided here courtesy of