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

Abstract

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 ERalpha or ERbeta, 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 ERalpha and ERbeta transactivation, and coactivator recruitment in human cells. The soy-derived genistein, coumestrol, and equol displayed a preference for transactivation of ERbeta compared to ERalpha and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ERalpha. 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 ERalpha and ERbeta. All phytoestrogens tested showed reduced potencies to activate ERalpha and ERbeta 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 ERalpha and ERbeta at high doses. The phytoestrogens enhanced preferentially recruitment of GRIP1 to ERalpha similar to 17beta-estradiol. In contrast, for ERbeta no distinct preference for one coactivator (GRIP1 or SRC-1) was apparent and the overall coactivator association was less pronounced than for ERalpha. 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.

Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

“…Although genestein has a greater affinity for the ERb than the ERa subtype (Kuiper et al, 1997;Kostelac et al, 2003;Mueller et al, 2004;Zhao and Brinton, 2005;McCarty, 2006), it does have the potential to act as a full agonist at both these ER subtypes (Mueller et al, 2004;McCarty, 2006). However, as the vaginal cytology of the OVX + DMSO control rats did not show any evidence of vaginal cornification, we do not believe that exposure to phytoestrogens in the rat food led to any significant activation of the ERa subtype.…”

Potential anti-inflammatory, anti-adhesive, anti/estrogenic, and angiotensin-converting enzyme inhibitory activities of anthocyanins and their gut metabolites

“…In general, the affinity of flavonoids to bind to ERa and b is lower than that of 17-bestradiol. However, some studies have confirmed that genistein, daidzein, and equol have a good affinity for ER, especially for ERb (Mueller et al 2004).…”

ERβ in breast cancer—Onlooker, passive player, or active protector?

“…AF-1 domains of each receptor play a critical role in their activity, but ligands determine biological responses [23][24][25][26]. SERMS, phytoestrogens, derivatives, and metabolites exhibit ER isoform specificity in binding and activation in different cell and promoter contexts [20][21][22][23][24][25].…”