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ToxSci Advance Access originally published online on April 14, 2004
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Toxicological Sciences 80, 14-25 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.

Phytoestrogens and Their Human Metabolites Show Distinct Agonistic and Antagonistic Properties on Estrogen Receptor {alpha} (ER{alpha}) and ERß in Human Cells

Stefan O. Mueller*,1, Stephanie Simon*, Kun Chae{dagger}, Manfred Metzler{ddagger} and Kenneth S. Korach{dagger}

* Molecular Toxicology, Institute of Toxicology, Merck KGaA, Darmstadt, Germany; {dagger} Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and {ddagger} Institute of Food Chemistry and Toxicology, University of Karlsruhe, Karlsruhe, Germany

Received January 9, 2004; accepted April 5, 2004

Phytoestrogens exert pleiotropic effects on cellular signaling and show some beneficial effects on estrogen-dependent diseases. However, due to activation/inhibition of the estrogen receptors ER{alpha} or ERß, these compounds may induce or inhibit estrogen action and, therefore, have the potential to disrupt estrogen signaling. We performed a comprehensive analysis and potency comparison of phytoestrogens and their human metabolites for ER binding, induction/suppression of ER{alpha} and ERß transactivation, and coactivator recruitment in human cells. The soy-derived genistein, coumestrol, and equol displayed a preference for transactivation of ERß compared to ER{alpha} and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ER{alpha}. All other phytoestrogens tested, including resveratrol and human metabolites of daidzein and enterolactone, were weak ER agonists. Interestingly, the daidzein metabolites 3',4',7-isoflavone and 4',6,7-isoflavone were superagonists on ER{alpha} and ERß. All phytoestrogens tested showed reduced potencies to activate ER{alpha} and ERß compared to diethylstilbestrol on the estrogen-responsive C3 promoter compared to a consensus estrogen response element indicating a degree of promoter dependency. Zearalenone and resveratrol were antagonistic on both ER{alpha} and ERß at high doses. The phytoestrogens enhanced preferentially recruitment of GRIP1 to ER{alpha} similar to 17ß-estradiol. In contrast, for ERß no distinct preference for one coactivator (GRIP1 or SRC-1) was apparent and the overall coactivator association was less pronounced than for ER{alpha}. Due to their abundance and (anti)-estrogenic potencies, the soy-derived isoflavones, coumestrol, resveratrol, and zearalenone would appear to have the potential for effectively functioning as endocrine disruptors.

Key Words: ER{alpha}; ERß; xenoestrogen; endocrine disruptors; Ishikawa; coactivator recruitment.


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