ToxSci Advance Access published online on April 14, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh147
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Molecular Toxicology, Institute of Toxicology, Merck KGaA, 64271 Darmstadt, Germany
* To whom correspondence should be addressed. E-mail: stefan.o.mueller{at}merck.de.
Phytoestrogens exert pleiotropic effects on cellular signaling and show in part beneficial effects on estrogen-dependent diseases. However, due to activation/inhibition of the estrogen receptors, ER
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Endocrine Toxicology
Phytoestrogens and Their Human Metabolites Show Distinct Agonistic and Antagonistic Properties on Estrogen Receptor (ER)
and ER
in Human Cells
2 Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
3 Institute of Food Chemistry and Toxicology, University of Karlsruhe, Germany
Abstract 
or ER
, these compounds may induce or inhibit estrogen action and have therefore the potential to disrupt estrogen signaling. We provide here a comprehensive analysis and potency comparison of phytoestrogens and their human metabolites for ER binding, induction/suppression of ER and ER transactivation and coactivator recruitment in human cells. The soy-derived genistein, coumestrol and equol displayed a preference for transactivation of ER compared to ER and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ER. All other phytoestrogens tested including resveratrol as well as human metabolites of daidzein and enterolactone were weak ER agonists. Interestingly, the daidzein metabolites 3',4',7-isoflavone and 4',6,7-isoflavone were super-agonists on ER and ER. All phytoestrogens tested showed reduced potencies to activate ER and ER 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 and ER at high doses. The phytoestrogens enhanced preferentially recruitment of GRIP1 to ER similar to 17-estradiol. In contrast, for ER no distinct preference for one coactivator (GRIP1 or SRC-1) was apparent and the overall coactivator association was less pronounced than for ER. 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., ER, xenoestrogen, endocrine disruptors, Ishikawa, coactivator recruitment
.
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