Isoflavones are safe compounds for therapeutical applications – Evaluation of in vitro data

References

• Iwasaki M, Inoue M, Otani T, Sasazuki S, Kurahashi N, Miura T, Yamamoto S, Tsugane S. Plasma isoflavone level and subsequent risk of breast cancer among Japanese women: a nested case-control study from the Japan Public Health Center-based prospective study group. J Clin Oncol 2008; 26: 1677–1683
   PubMed Web of Science ®Google Scholar
• Segars J H, Driggers P H. Estrogen action and cytoplasmic signaling cascades. I. Membrane-associated signaling complexes. Trends Endocrinol Metab 2002; 13: 349–354
   PubMed Web of Science ®Google Scholar
• Soto A M, Sonnenschein C, Chung K L, Fernandez M F, Olea N, Serrano F O. The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ Health Perspect 1995; 103: 113–122
   PubMed Web of Science ®Google Scholar
• Metzger D, White J H, Chambon P. The human oestrogen receptor functions in yeast. Nature 1988; 334: 31–36
   PubMed Web of Science ®Google Scholar
• Fang H, Tong W, Shi L M, Blair R, Perkins R, Branham W, Hass B S, Xie Q, Dial S L, Moland C L, et al. Structure–activity relationships for a large diverse set of natural, synthetic, and environmental estrogens. Chem Res Toxicol 2001; 14: 280–294
   PubMed Web of Science ®Google Scholar
• Choi S Y, Ha T Y, Ahn J Y, Kim S R, Kang K S, Hwang I K, Kim S. Estrogenic activities of isoflavones and flavones and their structure–activity relationships. Planta Med 2008; 74: 25–32
   PubMed Web of Science ®Google Scholar
• Kuiper G GJM, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson J-A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors {alpha} and {beta}. Endocrinology 1997; 138: 863–870
   PubMed Web of Science ®Google Scholar
• Collins B M, McLachlan J A, Arnold S F. The estrogenic and antiestrogenic activities of phytochemicals with the human estrogen receptor expressed in yeast. Steroids 1997; 62: 365–372
   PubMed Web of Science ®Google Scholar
• Liu J, Burdette J E, Xu H, Gu C, van Breemen R B, Bhat K P, Booth N, Constantinou A I, Pezzuto J M, Fong H H, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001; 49: 2472–2479
   PubMed Web of Science ®Google Scholar
• Breithofer A, Graumann K, Scicchitano M S, Karathanasis S K, Butt T R, Jungbauer A. Regulation of human estrogen receptor by phytoestrogens in yeast and human cells. J Steroid Biochem Mol Biol 1998; 67: 421–429
   PubMed Web of Science ®Google Scholar
• Beck V, Unterrieder E, Krenn L, Kubelka W, Jungbauer A. Comparison of hormonal activity (estrogen, androgen and progestin) of standardized plant extracts for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol 2003; 84: 259–268
   PubMed Web of Science ®Google Scholar
• Jungbauer A, Beck V. Yeast reporter system for rapid determination of estrogenic activity. J Chromatogr B Anal Technol Biomed Life Sci 2002; 777: 167–178
   PubMed Web of Science ®Google Scholar
• Breinholt V, Larsen J C. Detection of weak estrogenic flavonoids using a recombinant yeast strain and a modified MCF7 cell proliferation assay. Chem Res Toxicol 1998; 11: 622–629
   PubMed Web of Science ®Google Scholar
• Promberger A, Dornstauder E, Fruhwirth C, Schmid E R, Jungbauer A. Determination of estrogenic activity in beer by biological and chemical means. J Agric Food Chem 2001; 49: 633–640
   PubMedGoogle Scholar
• Dornstauder E, Jisa E, Unterrieder I, Krenn L, Kubelka W, Jungbauer A. Estrogenic activity of two standardized red clover extracts (Menoflavon) intended for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol 2001; 78: 67–75
   PubMed Web of Science ®Google Scholar
• Miksicek R J. Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor. J Steroid Biochem Mol Biol 1994; 49: 153–160
   PubMed Web of Science ®Google Scholar
• Hwang C S, Kwak H S, Lim H J, Lee S H, Kang Y S, Choe T B, Hur H G, Han K O. Isoflavone metabolites and their in vitro dual functions: they can act as an estrogenic agonist or antagonist depending on the estrogen concentration. J Steroid Biochem Mol Biol 2006; 101: 246–253
   PubMed Web of Science ®Google Scholar
• Kostelac D, Rechkemmer G, Briviba K. Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. J Agric Food Chem 2003; 51: 7632–7635
   PubMed Web of Science ®Google Scholar
• Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag P T, van der Burg B, Gustafsson J A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998; 139: 4252–4263
   PubMed Web of Science ®Google Scholar
• Song T T, Hendrich S, Murphy P A. Estrogenic activity of glycitein, a soy isoflavone. J Agric Food Chem 1999; 47: 1607–1610
   PubMed Web of Science ®Google Scholar
• Zhang Y, Song T T, Cunnick J E, Murphy P A, Hendrich S. Daidzein and genistein glucuronides in vitro are weakly estrogenic and activate human natural killer cells at nutritionally relevant concentrations. J Nutr 1999; 129: 399–405
   PubMed Web of Science ®Google Scholar
• Muthyala R S, Ju Y H, Sheng S, Williams L D, Doerge D R, Katzenellenbogen B S, Helferich W G, Katzenellenbogen J A. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem 2004; 12: 1559–1567
   PubMed Web of Science ®Google Scholar
• Milligan S R, Kalita J C, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 1999; 84: 2249–2252
   PubMed Web of Science ®Google Scholar
• Bovee T FH, Helsdingen R JR, Rietjens I MCM, Keijer J, Hoogenboom R LAP. Rapid yeast estrogen bioassays stably expressing human estrogen receptors [alpha] and [beta], and green fluorescent protein: a comparison of different compounds with both receptor types. J Steroid Biochem Mol Biol 2004; 91: 99–109
   PubMed Web of Science ®Google Scholar
• Federici E, Touche A, Choquart S, Avanti O, Fay L, Offord E, Courtois D. High isoflavone content and estrogenic activity of 25 year-old Glycine max tissue cultures. Phytochemistry 2003; 64: 717–724
   PubMedGoogle Scholar
• Chrzan B G, Bradford P G. Phytoestrogens activate estrogen receptor β1 and estrogenic responses in human breast and bone cancer cell lines. Mol Nutr Food Res 2007; 51: 171–177
   PubMed Web of Science ®Google Scholar
• Harris D M, Besselink E, Henning S M, Go V LW, Heber D. Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells. Exp Biol Med 2005; 230: 558–568
   PubMed Web of Science ®Google Scholar
• 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 estrogenic responses in human cells. Toxicol Sci 2004; 80: 14–25
   PubMed Web of Science ®Google Scholar
• Gutendorf B, Westendorf J. Comparison of an array of in vitro assays for the assessment of the estrogenic potential of natural and synthetic estrogens, phytoestrogens and xenoestrogens. Toxicology 2001; 166: 79–89
   PubMed Web of Science ®Google Scholar
• Hunter D S, Hodges L C, Vonier P M, Fuchs-Young R, Gottardis M M, Walker C L. Estrogen receptor activation via activation function 2 predicts agonism of xenoestrogens in normal and neoplastic cells of the uterine myometrium. Cancer Res 1999; 59: 3090–3099
   PubMedGoogle Scholar
• Arnold S F, Collins B M, Robinson M K, Guillette L J, Jr, McLachlan J A. Differential interaction of natural and synthetic estrogens with extracellular binding proteins in a yeast estrogen screen. Steroids 1996; 61: 642–646
   PubMedGoogle Scholar
• Hasenbrink G, Sievernich A, Wildt L, Ludwig J, Lichtenberg-Frate H. Estrogenic effects of natural and synthetic compounds including tibolone assessed in Saccharomyces cerevisiae expressing the human estrogen {alpha} and {beta} receptors. FASEB J 2006; 20: 1552–1554
   PubMedGoogle Scholar
• Sonneveld E, Jansen H J, Riteco J AC, Brouwer A, van der Burg B. Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci 2005; 83: 136–148
   PubMed Web of Science ®Google Scholar
• Hsieh R W, Rajan S S, Sharma S K, Guo Y, DeSombre E R, Mrksich M, Greene G L. Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. J Biol Chem 2006; 281: 17909–17919
   PubMed Web of Science ®Google Scholar
• Kuiper G GJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J A. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996; 93: 5925–5930
   PubMed Web of Science ®Google Scholar
• Enmark K, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson J A. Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997; 82: 4258–4265
   PubMed Web of Science ®Google Scholar
• Clarke R B, Howell A, Potten C S, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 1997; 57: 4987–4991
   PubMed Web of Science ®Google Scholar
• Saunders P TK, Millar M R, Williams K, Macpherson S, Bayne C, O'Sullivan C, Anderson T J, Groome N P, Miller W R. Expression of oestrogen receptor beta (ERβI) protein in human breast cancer biopsies. Br J Cancer 2002; 86: 250–256
   PubMedGoogle Scholar
• Middleton L P, Perkins G H, Tucker S L, Sahin A A, Singletary S E. Expression of ERα AND β in lobular carcinoma in situ. Histopathology 2007; 50: 875–880
   PubMedGoogle Scholar
• Murphy C E, Carder P J, Lansdown M RJ, Speirs V. Steroid hormone receptor expression in male breast cancer. Eur J Surg Oncol 2006; 32: 44–47
   PubMed Web of Science ®Google Scholar
• Saji S, Hirose M, Toi M. Clinical significance of estrogen receptor β in breast cancer. Cancer Chemother Pharmacol 2005; 56: s21–s26
   PubMedGoogle Scholar
• Skliris G P, Leygue E, Curtis-Snell L, Watson P H, Murphy L C. Expression of oestrogen receptor-β in oestrogen receptor-α negative human breast tumours. Br J Cancer 2006; 95: 616–626
   PubMedGoogle Scholar
• Skliris G P, Leygue E, Watson P H, Murphy L C. Estrogen receptor alpha negative breast cancer patients: estrogen receptor beta as a therapeutic target. J Steroid Biochem and Mol Biol 2008; 109: 1–10
   PubMed Web of Science ®Google Scholar
• Behrens D, Gill J H, Fichtner I. Loss of tumourigenicity of stably ERβ-transfected MCF-7 breast cancer cells. Mol Cellular Endocrinol 2007; 274: 19–29
   PubMedGoogle Scholar
• Paech K, Webb P, Kuiper G GJM, Nilsson S, Gustafsson J A, Kushner P J, Scanlan T S. Differential ligand activation of estrogen receptors ERβ at AP1 sites. Science 1997; 277: 1508–1510
   PubMed Web of Science ®Google Scholar
• Gougelet A, Mueller S O, Korach K S, Renoir J M. Oestrogen receptors pathways to oestrogen responsive elements: the transactivation function-1 acts as the keystone of oestrogen receptor (ER)β-mediated transcriptional repression of ERα. J Steroid Biochem Mol Biol 2007; 104: 110–112
   PubMedGoogle Scholar
• Day J K, Besch-Williford C, McMann T R, Hufford M G, Lubahn D B, MacDonald R S. Dietary genistein increased DMBA-induced mammary adenocarcinoma in wild-type, but not ERαKO, mice. Nutr Cancer 2001; 39: 226–232
   PubMed Web of Science ®Google Scholar
• Routledge E J, White R, Parker M G, Sumpter J P. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta. J Biol Chem 2000; 275: 35986–35993
   PubMed Web of Science ®Google Scholar
• Chang E C, Charn T H, Park S-H, Helferich W G, Komm B, Katzenellenbogen J A, Katzenellenbogen B S. Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol 2008; 22: 1032–1043
   PubMed Web of Science ®Google Scholar
• Brooks J D, Thompson L U. Mammalian lignans and genistein decrease the activities of aromatase and 17[beta]-hydroxysteroid dehydrogenase in MCF-7 cells. J Steroid Biochem Mol Biol 2005; 94: 461–467
   PubMed Web of Science ®Google Scholar
• Almstrup K, Fernández M F, Petersen J H, Olea N, Skakkebæk N E, Leffers H. Dual effects of phytoestrogens result in U-shaped dose-response curves. Environ Health Perspect 2002; 110: 743–748
   PubMed Web of Science ®Google Scholar
• Wang Y, Man Gho W, Chan F L, Chen S, Leung L K. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr 2007; 99: 303–310
   PubMedGoogle Scholar
• Whitehead S A, Lacey M. Phytoestrogens inhibit aromatase but not 17{beta}-hydroxysteroid dehydrogenase (HSD) type 1 in human granulosa-luteal cells: evidence for FSH induction of 17{beta}-HSD. Hum Reprod 2003; 18: 487–494
   PubMed Web of Science ®Google Scholar
• Brueggemeier R W, Gu X, Mobley J A, Joomprabutra S, Bhat A S, Whetstone J L. Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism. Ann N Y Acad Sci 2001; 948: 51–66
   PubMedGoogle Scholar
• Mäkelä S, Poutanen M, Lehtimaki J, Kostian M L, Santti R, Vihko R. Estrogen-specific 17 beta-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: 51–59
   PubMed Web of Science ®Google Scholar
• Blomquist C H, Lima P H, Hotchkiss J R. Inhibition of 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C 18-, C19- and C21-hydroxysteroids and ketosteroids. Steroids 2005; 70: 507–514
   PubMed Web of Science ®Google Scholar
• Kirk C J, Harris R M, Wood D M, Waring R H, Hughes P J. Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens?. Biochem Soc Trans 2001; 29: 209–216
   PubMed Web of Science ®Google Scholar
• Harris R M, Wood D M, Bottomley L, Blagg S, Owen K, Hughes P J, Waring R H, Kirk C J. Phytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatment. J Clin Endocrinol Metab 2004; 89: 1779–1787
   PubMed Web of Science ®Google Scholar
• Loaiza-Perez A I, Trapani V, Hose C, Singh S S, Trepel J B, Stevens M FG, Bradshaw T D, Sausville E A. Aryl hydrocarbon receptor mediates sensitivity of MCF-7 breast cancer cells to antitumor agent 2-(4-amino-3-methylphenyl) benzothiazole. Mol Pharmacol 2002; 61: 13–19
   PubMed Web of Science ®Google Scholar
• Safe S, Wormke M, Samudio I. Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells. J Mammary Gland Biol Neoplasia 2000; 5: 295
   PubMed Web of Science ®Google Scholar
• Chua M S, Kashiyama E, Bradshaw T D, Stinson S F, Brantley E, Sausville E A, Stevens M FG. Role of CYP1A1 in modulation of antitumor properties of the novel agent 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) in human breast cancer cells. Cancer Res 2000; 60: 5196–5203
   PubMed Web of Science ®Google Scholar
• Ashida H. Suppressive effects of flavonoids on dioxin toxicity. BioFactors 2000; 12: 201
   PubMed Web of Science ®Google Scholar
• Kajta M, Domin H, Grynkiewicz G, Lason W. Genistein inhibits glutamate-induced apoptotic processes in primary neuronal cell cultures: an involvement of aryl hydrocarbon receptor and estrogen receptor/glycogen synthase kinase-3β intracellular signaling pathway. Neuroscience 2007; 145: 592–604
   PubMed Web of Science ®Google Scholar
• Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347: 645–650
   PubMed Web of Science ®Google Scholar
• Ginsberg H N, Le N A, Goldberg I J, Gibson J C, Rubinstein A, Wang-Iverson P, Norum R, Brown W V. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 1986; 78: 1287–1295
   PubMed Web of Science ®Google Scholar
• Li A C, Binder C J, Gutierrez A, Brown K K, Plotkin C R, Pattison J W, Valledor A F, Davis R A, Willson T M, Witztum J L, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ and γ. J Clin Investig 2004; 114: 1564–1576
   PubMed Web of Science ®Google Scholar
• Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307–312
   PubMed Web of Science ®Google Scholar
• Chacko B K, Chandler R T, D'Alessandro T L, Mundhekar A, Khoo N KH, Botting N, Barnes S, Patel R P. Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPARγ. J Nutr 2007; 137: 351–356
   PubMedGoogle Scholar
• 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. J Nutr Biochem 2005; 16: 321–330
   PubMed Web of Science ®Google Scholar
• Kwon D Y, Jang J S, Lee J E, Kim Y S, Shin D H, Park S. The isoflavonoid aglycone-rich fractions of Chungkookjang, fermented unsalted soybeans, enhance insulin signaling and peroxisome proliferator-activated receptor-γ activity in vitro. BioFactors 2006; 26: 245–258
   PubMedGoogle Scholar
• Dang Z C, Audinot V, Boutin J A, Lowik C WGM. Peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 2003; 278: 962–967
   PubMed Web of Science ®Google Scholar
• Kim S, Shin H J, Kim S Y, Kim J H, Lee Y S, Kim D H, Lee M O. Genistein enhances expression of genes involved in fatty acid catabolism through activation of PPARα. Mol Cellular Endocrinol 2004; 220: 51–58
   PubMed Web of Science ®Google Scholar
• Mezei O, Banz W J, Steger R W, Peluso M R, Winters T A, Shay N. Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells. J Nutr 2003; 133: 1238–1243
   PubMed Web of Science ®Google Scholar
• Shen P, Liu M H, Ng T Y, Chan Y H, Yong E L. Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the activation of PPARα, PPARγ, and adipocyte differentiation in vitro. J Nutr 2006; 136: 899–905
   PubMed Web of Science ®Google Scholar
• Dang Z, Lowik C WGM. The balance between concurrent activation of ERs and PPARs determines daidzein-induced osteogenesis and adipogenesis. J Bone Miner Res 2004; 19: 853–861
   PubMed Web of Science ®Google Scholar
• Rayalam S, Della-Fera M A, Yang J Y, Hea J P, Ambati S, Baile C A. Resveratrol potentiates genistein's antiadipogenic and proapoptotic effects in 3T3-L1 adipocytes. J Nutr 2007; 137: 2668–2673
   PubMedGoogle Scholar
• Szkudelska K, Nogowski L, Szkudelski T. Genistein, a plant-derived isoflavone, counteracts the antilipolytic action of insulin in isolated rat adipocytes. J Steroid Biochem Mol Biol 2008; 109: 108–114
   PubMed Web of Science ®Google Scholar
• Shimba S, Wada T, Tezuka M. Arylhydrocarbon receptor (AhR) is involved in negative regulation of adipose differentiation in 3T3-L1 cells: AhR inhibits adipose differentiation independently of dioxin. J Cell Sci 2001; 114: 2809–2817
   PubMed Web of Science ®Google Scholar
• Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, et al. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci USA 2005; 102: 10610–10615
   PubMed Web of Science ®Google Scholar
• Klöting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schön M R, Stumvoll M, Blüher M. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem Biophys Res Commun 2006; 339: 430–436
   PubMed Web of Science ®Google Scholar
• Rachon D, Mysliwska J, Suchecka-Rachon K, Wieckiewicz J, Mysliwski A. Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. J Endocrinol 2002; 172: 387–395
   PubMed Web of Science ®Google Scholar
• Masiukiewicz U S, Mitnick M, Grey A B, Insogna K L. Estrogen modulates parathyroid hormone-induced interleukin-6 production in vivo and in vitro. Endocrinology 2000; 141: 2526–2531
   PubMedGoogle Scholar
• Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou N A. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003; 32: 1–7
   PubMed Web of Science ®Google Scholar
• Nuttall M E, Gimble J M. Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis?. Bone 2000; 27: 177–184
   PubMed Web of Science ®Google Scholar
• Heim M, Frank O, Kampmann G, Sochocky N, Pennimpede T, Fuchs P, Hunziker W, Weber P, Martin I, Bendik I. The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. Endocrinology 2004; 145: 848–859
   PubMed Web of Science ®Google Scholar
• Li X H, Zhang J C, Sui S F, Yang M S. Effect of daidzin, genistin, and glycitin on osteogenic and adipogenic differentiation of bone marrow stromal cells and adipocytic transdifferentiation of osteoblasts. Acta Pharmacol Sin 2005; 26: 1081–1086
   PubMed Web of Science ®Google Scholar
• Schmitt E, Dekant W, Stopper H. Assaying the estrogenicity of phytoestrogens in cells of different estrogen sensitive tissues. Toxicol in Vitro 2001; 15: 433–439
   PubMed Web of Science ®Google Scholar
• Allred C D, Allred K F, Ju Y H, Virant S M, Helferich W G. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Res 2001; 61: 5045–5050
   PubMed Web of Science ®Google Scholar
• Hsieh C Y, Santell R C, Haslam S Z, Helferich W G. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 1998; 58: 3833–3838
   PubMed Web of Science ®Google Scholar
• Ju Y H, Allred C D, Allred K F, Karko K L, Doerge D R, Helferich W G. Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. J Nutr 2001; 131: 2957–2962
   PubMed Web of Science ®Google Scholar
• Maggiolini M, Bonofiglio D, Marsico S, Panno M L, Cenni B, Picard D, Andò S. Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Mol Pharmacol 2001; 60: 595–602
   PubMed Web of Science ®Google Scholar
• Seo H S, DeNardo D G, Jacquot Y, Laios I, Vidal D S, Zambrana C R, Leclercq G, Brown P H. Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat 2006; 99: 121–134
   PubMed Web of Science ®Google Scholar
• van Meeuwen J A, ter Burg W, Piersma A H, van der Berg M, Sanderson J T. Mixture effects of estrogenic compounds on proliferation and pS2 expression of MCF-7 human breast cancer cells. Food Chem Toxicol 2007; 45: 2319–2330
   PubMed Web of Science ®Google Scholar
• Wang T TY, Sathyamoorthy N, Phang J M. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996; 17: 271–275
   PubMed Web of Science ®Google Scholar
• Wang W, Tanaka Y, Han Z, Higuchi C M. Proliferative response of mammary glandular tissue to formononetin. Nutr Cancer 1995; 23: 131–140
   PubMed Web of Science ®Google Scholar
• Guo J M, Xiao B X, Liu D H, Grant M, Zhang S, Lai Y F, Guo Y B, Liu Q. Biphasic effect of daidzein on cell growth of human colon cancer cells. Food Chem Toxicol 2004; 42: 1641–1646
   PubMed Web of Science ®Google Scholar
• Yin C P, Fan L C, He J W, Liu M N, Wang Y Q, Zhang Z Y. Effect of red clover total isoflavones on cell proliferation and apoptosis of human breast cancer cell line MCF-7. Chin Traditional Herbal Drugs 2007; 38: 232–234
   Google Scholar
• Bochar D A, Wang L, Beniya H, Kinev A, Xue Y, Lane W S, Wang W, Kashanchi F, Shiekhattar R. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 2000; 102: 257–265
   PubMed Web of Science ®Google Scholar
• Chiba N, Parvin J D. Redistribution of BRCA1 among four different protein complexes following replication blockage. J Biol Chem 2001; 276: 38549–38554
   PubMedGoogle Scholar
• Le Page F, Randrianarison V, Marot D, Cabannes J, Perricaudet M, Feunteun J, Sarasin A. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res 2000; 60: 5548–5552
   PubMed Web of Science ®Google Scholar
• Patel K J, Yu V PCC, Lee H, Corcoran A, Thistlethwaite F C, Evans M J, Colledge W H, Friedman L S, Ponder B AJ, Venkitaraman A R. Involvement of Brca2 in DNA repair. Mol Cell 1998; 1: 347–357
   PubMed Web of Science ®Google Scholar
• Venkitaraman A R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002; 108: 171–182
   PubMed Web of Science ®Google Scholar
• Venkitaraman A R. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci 2001; 114: 3591–3598
   PubMed Web of Science ®Google Scholar
• Bonorden M JL, Greany K A, Wangen K E, Feirtag J, Kurzer M S, Phipps W R, Adlercreutz H. Consumption of Lactobacillus acidophilus and Bifidobacterium longum do not alter urinary equol excretion and plasma reproductive hormones in premenopausal women. Eur J Clin Nutr 2004; 58: 1635
   PubMed Web of Science ®Google Scholar
• Wang Y, Cortez D, Yazdi P, Neff N, Elledge S J, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000; 14: 927–939
   PubMed Web of Science ®Google Scholar
• Caetano B, Le Corre L, Chalabi N, Delort L, Bignon Y J, Bernard-Gallon D J. Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines. Br J Nutr 2006; 95: 406–413
   PubMed Web of Science ®Google Scholar
• Fan S, Meng Q, Auborn K, Carter T, Rosen E M. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 2006; 94: 407–426
   Google Scholar
• Li Y, Ahmed F, Ali S, Philip P A, Kucuk O, Sarkar F H. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res 2005; 65: 6934–6942
   PubMed Web of Science ®Google Scholar
• Li Y, Bhuiyan M, Sarkar F H. Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. Int J Oncol 1999; 15: 525–533
   PubMed Web of Science ®Google Scholar
• Li Y, Upadhyay S, Bhuiyan M, Sarkar F H. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 1999; 18: 3166–3172
   PubMed Web of Science ®Google Scholar
• Mai Z, Blackburn G L, Zhou J R. Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Mol Carcinog 2007; 46: 534–542
   PubMed Web of Science ®Google Scholar
• Mak P, Leung Y K, Tang W Y, Harwood C, Ho S M. Apigenin suppresses cancer cell growth through ERbeta. Neoplasia 2006; 8: 896–904
   PubMed Web of Science ®Google Scholar
• Peterson G, Barnes S. Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochem Biophys Res Commun 1991; 179: 661–667
   PubMed Web of Science ®Google Scholar
• Raffoul J J, Wang Y, Kucuk O, Forman J D, Sarkar F H, Hillman G G. Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest. BMC Cancer 2006; 6: 107
   PubMed Web of Science ®Google Scholar
• Shao Z M, Alpaugh M L, Fontana J A, Barsky S H. Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21WAF1/CIP1 induction, G2/M arrest, and apoptosis. J Cell Biochem 1998; 69: 44–54
   PubMed Web of Science ®Google Scholar
• Shao Z M, Wu J, Shen Z Z, Barsky S H. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 1998; 58: 4851–4857
   PubMed Web of Science ®Google Scholar
• Upadhyay S, Neburi M, Chinni S R, Alhasan S, Miller F, Sarkar F H. Differential sensitivity of normal and malignant breast epithelial cells to genistein is partly mediated by p21(WAF1). Clin Cancer Res 2001; 7: 1782–1789
   PubMed Web of Science ®Google Scholar
• Yang S, Zhou Q, Yang X. Caspase-3 status is a determinant of the differential responses to genistein between MDA-MB-231 and MCF-7 breast cancer cells. Biochim Biophys Acta 2007; 1773: 903–911
   PubMed Web of Science ®Google Scholar
• Davis N J, Singh B, Bhuiyan M, Sarkar F H. Genistein-induced upregulation of p21WAF1, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 1998; 32: 123–131
   PubMed Web of Science ®Google Scholar
• Zhou J R, Gugger E T, Tanaka T, Guo Y, Blackburn G L, Clinton S K. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 1999; 129: 1628–1635
   PubMed Web of Science ®Google Scholar
• Yu Z, Li W, Liu F. Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells. Cancer Lett 2004; 215: 159–166
   PubMed Web of Science ®Google Scholar
• Su S-J, Yeh T-M, Lei H-Y, Chow N-H. The potential of soybean foods as a chemoprevention approach for human urinary tract cancer. Clin Cancer Res 2000; 6: 230–236
   PubMed Web of Science ®Google Scholar
• Bergamaschi G, Rosti V, Danova M, Ponchio L, Lucotti C, Cazzola M. Inhibitors of tyrosine phosphorylation induce apoptosis in human leukemic cell lines. Leukemia 1993; 7: 2012–2018
   PubMed Web of Science ®Google Scholar
• Jin C Y, Park C, Cheong J, Choi B T, Lee T H, Lee J D, Lee W H, Kim G Y, Ryu C H, Choi Y H. Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. Cancer Lett 2007; 257: 56–64
   PubMed Web of Science ®Google Scholar
• 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: 5815–5821
   PubMed Web of Science ®Google Scholar
• Lian F, Bhuiyan M, Li Y W, Wall N, Kraut M, Sarkar F H. Genistein-induced G2-M arrest, p21WAF1 upregulation, and apoptosis in a non-small-cell lung cancer cell line. Nutr Cancer 1998; 31: 184–191
   PubMed Web of Science ®Google Scholar
• Lian F, Li Y, Bhuiyan M, Sarkar F H. p53-independent apoptosis induced by genistein in lung cancer cells. Nutr Cancer 1999; 33: 125–131
   PubMed Web of Science ®Google Scholar
• Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar F H. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006; 5: 483–493
   PubMed Web of Science ®Google Scholar
• Chang K L, Kung M L, Chow N H, Su S J. Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21waf1/cip1 and Wee1. Biochem Pharmacol 2004; 67: 717–726
   PubMed Web of Science ®Google Scholar
• Chodon D, Ramamurty N, Sakthisekaran D. Preliminary studies on induction of apoptosis by genistein on HepG2 cell line. Toxicol In Vitro 2007; 21: 887–891
   PubMed Web of Science ®Google Scholar
• Gu Y, Zhu C F, Iwamoto H, Chen J S. Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis. World J Gastroenterol 2005; 11: 6512–6517
   PubMed Web of Science ®Google Scholar
• Sasamura H, Takahashi A, Yuan J, Kitamura H, Masumori N, Miyao N, Itoh N, Tsukamoto T. Antiproliferative and antiangiogenic activities of genistein in human renal cell carcinoma. Urology 2004; 64: 389–393
   PubMed Web of Science ®Google Scholar
• Guo J M, Kang G Z, Xiao B X, Liu D H, Zhang S. Effect of daidzein on cell growth, cell cycle, and telomerase activity of human cervical cancer in vitro. Int J Gynecol Cancer 2004; 14: 882–888
   PubMedGoogle Scholar
• Wu C P, Calcagno A M, Hladky S B, Ambudkar S V, Barrand M A. Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). FEBS J 2005; 272: 4725–4740
   PubMed Web of Science ®Google Scholar
• Atkin G K, Chopada A. Tumour angiogenesis: the relevance to surgeons. Ann Royal Coll Surg England 2006; 88: 525–529
   PubMedGoogle Scholar
• Griffioen A W, Molema G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 2000; 52: 237–268
   PubMed Web of Science ®Google Scholar
• Bikfalvi A. Platelet factor 4: an inhibitor of angiogenesis. Semin Thromb Hemostasis 2004; 30: 379–385
   PubMed Web of Science ®Google Scholar
• Su S J, Yeh T M, Chuang W J, Ho C L, Chang K L, Cheng K L, Liu H S, Cheng H L, Hsu P Y, Chow N H. The novel targets for anti-angiogenesis of genistein on human cancer cells. Biochem Pharmacol 2005; 69: 307–318
   PubMed Web of Science ®Google Scholar
• Guo Y, Wang S, Hoot D R, Clinton S K. Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer cells and vascular endothelial cells by soy isoflavones. J Nutr Biochem 2007; 18: 408–417
   PubMed Web of Science ®Google Scholar
• Piao M, Mori D, Satoh T, Sugita Y, Tokunaga O. Inhibition of endothelial cell proliferation, in vitro angiogenesis, and the down-regulation of cell adhesion-related genes by genistein. Combined with a cDNA microarray analysis. Endothelium 2006; 13: 249–266
   PubMed Web of Science ®Google Scholar
• Büchler P, Reber H A, Büchler M W, Friess H, Lavey R S, Hines O J. Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression. Cancer 2004; 100: 201–210
   PubMedGoogle Scholar
• Huang X, Chen S, Xu L, Liu Y, Deb D K, Platanias L C, Bergan R C. Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res 2005; 65: 3470–3478
   PubMed Web of Science ®Google Scholar
• Feghali C A, Wright T M. Cytokines in acute and chronic inflammation. Frontiers Biosci 1997; 2: d12–d26
   PubMedGoogle Scholar
• Koj A. Initiation of acute phase response and synthesis of cytokines. Biochim Biophys Acta 1996; 1317: 84–94
   PubMed Web of Science ®Google Scholar
• Vande Berghe W, De Bosscher K, Boone E, Plaisance S, Haegeman G. The nuclear factor-κB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem 1999; 274: 32091–32098
   PubMedGoogle Scholar
• Vanden Berghe W, Plaisance S, Boone E, De Bosscher K, Schmitz M L, Fiers W, Haegeman G. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-κB p65 transactivation mediated by tumor necrosis factor. J Biol Chem 1998; 273: 3285–3290
   PubMed Web of Science ®Google Scholar
• Verhasselt V, Vanden Berghe W, Vanderheyde N, Willems F, Haegeman G, Goldman M. N-acetyl-l-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-κB inhibition. J Immunol 1999; 162: 2569–2574
   PubMed Web of Science ®Google Scholar
• Raschke M, Rowland I R, Magee P J, Pool-Zobel B L. Genistein protects prostate cells against hydrogen peroxide-induced DNA damage and induces expression of genes involved in the defence against oxidative stress. Carcinogenesis 2006; 27: 2322–2330
   PubMed Web of Science ®Google Scholar
• Li Y, Ellis K L, Ali S, El-Rayes B F, Nedeljkovic-Kurepa A, Kucuk O, Philip P A, Sarkar F H. Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line. Pancreas 2004; 28: e90–e95
   Google Scholar
• Chen X, Anderson J J. Isoflavones inhibit proliferation of ovarian cancer cells in vitro via an estrogen receptor-dependent pathway. Nutr Cancer 2001; 41: 165–171
   PubMed Web of Science ®Google Scholar
• Vanden Berghe W, Dijsselbloem N, Vermeulen L, Ndlovu M N, Boone E, Haegeman G. Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity. Cancer Res 2006; 66: 4852–4862
   PubMed Web of Science ®Google Scholar
• Thompson D, Whicher J T, Evans S W. Interleukin 6 signal transduction in a human hepatoma cell line (Hep G2). Immunopharmacol Immunotoxicol 1993; 15: 371–386
   PubMedGoogle Scholar
• Parikh A A, Salzman A L, Kane C D, Fischer J E, Hasselgren P O. IL-6 production in human intestinal epithelial cells following stimulation with IL-1 beta is associated with activation of the transcription factor NF-kappa B. J Surg Res 1997; 69: 139–144
   PubMedGoogle Scholar
• Pool-Zobel B L, Adlercreutz H, Glei M, Liegibel U M, Sittlingon J, Rowland I, Wähälä K, Rechkemmer G. Isoflavonoids and lignans have different potentials to modulate oxidative genetic damage in human colon cells. Carcinogenesis 2000; 21: 1247–1252
   PubMed Web of Science ®Google Scholar
• Constantinou A I, Krygier A E, Mehta R R. Genistein induces maturation of cultured human breast cancer cells and prevents tumor growth in nude mice. Am J Clin Nutr 1998; 68: 1426S–1430S
   PubMed Web of Science ®Google Scholar
• Vantyghem S A, Wilson S M, Postenka C O, Al-Katib W, Tuck A B, Chambers A F. Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model. Cancer Res 2005; 65: 3396–3403
   PubMed Web of Science ®Google Scholar
• Mohammad R M, Banerjee S, Li Y, Aboukameel A, Kucuk O, Sarkar F H. Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts. Cancer 2006; 106: 1260–1268
   PubMedGoogle Scholar
• Rice L, Samedi V G, Medrano T A, Sweeney C A, Baker H V, Stenstrom A, Furman J, Shiverick K T. Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate 2002; 52: 201–212
   PubMedGoogle Scholar
• Ju Y H, Fultz J, Allred K F, Doerge D R, Helferich W G. Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice. Carcinogenesis 2006; 27: 856–863
   PubMed Web of Science ®Google Scholar
• Ju Y H, Doerge D R, Helferich W G. A dietary supplement for female sexual dysfunction, Avlimil, stimulates the growth of estrogen-dependent breast tumors (MCF-7) implanted in ovariectomized athymic nude mice. Food Chem Toxicol 2008; 46: 310–320
   PubMedGoogle Scholar
• Banerjee S, Zhang Y, Wang Z, Che M, Chiao P J, Abbruzzese J L, Sarkar F H. In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int J Cancer 2007; 120: 906–917
   PubMed Web of Science ®Google Scholar
• Chung S Y, Sung M K, Kim N H, Jang J O, Go E J, Lee H J. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch Pharm Res 2005; 28: 823–828
   PubMed Web of Science ®Google Scholar
• Cole S PC, Bhardwaj G, Gerlach J H, Mackie J E, Grant C E, Almquist K C, Stewart A J, Kurz E U, Duncan A MV, Deeley R G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258: 1650–1654
   PubMed Web of Science ®Google Scholar
• Raffoul J J, Banerjee S, Che M, Knoll Z E, Doerge D R, Abrams J, Kucuk O, Sarkar F H, Hillman G G. Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model. Int J Cancer 2007; 120: 2491–2498
   PubMed Web of Science ®Google Scholar
• Raffoul J J, Banerjee S, Singh-Gupta V, Knoll Z E, Fite A, Zhang H, Abrams J, Sarkar F H, Hillman G G. Down-regulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 expression by soy isoflavones enhances prostate cancer radiotherapy in vitro and in vivo. Cancer Res 2007; 67: 2141–2149
   PubMed Web of Science ®Google Scholar
• Shen J, Tai Y P, Zhou J, Stephen Wong C H, Cheang P T, Fred Wong W S, Xie Z, Khan M, Han J H, Chen C S. Synergistic antileukemia effect of genistein and chemotherapy in mouse xenograft model and potential mechanism through MAPK signaling. Exp Hematol 2007; 35: 75–83
   PubMed Web of Science ®Google Scholar
• Versantvoort C H, Schuurhuis G J, Pinedo H M, Eekman C A, Kuiper C M, Lankelma J, Broxterman H J. Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells. Br J Cancer 1993; 68: 939–946
   PubMed Web of Science ®Google Scholar
• Zhang S, Morris M E. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther 2003; 304: 1258–1267
   PubMed Web of Science ®Google Scholar
• Juliano R L, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 445: 152–162
   Web of Science ®Google Scholar
• Kartner N, Riordan J R, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 1983; 221: 1285–1288
   PubMed Web of Science ®Google Scholar
• Zhang S, Yang X, Morris M E. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol 2004; 65: 1208–1216
   PubMed Web of Science ®Google Scholar