Mueller Stefan O, Simon Stephanie, Chae Kun, Metzler Manfred, Korach Kenneth S
Molecular Toxicology, Institute of Toxicology, Merck KGaA, Darmstadt, Germany.
Toxicol Sci. 2004 Jul;80(1):14-25. doi: 10.1093/toxsci/kfh147. Epub 2004 Apr 14.
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.
植物雌激素对细胞信号传导具有多效性作用，并对雌激素依赖性疾病显示出一些有益效果。然而，由于激活/抑制雌激素受体ERα或ERβ，这些化合物可能诱导或抑制雌激素作用，因此有可能扰乱雌激素信号传导。我们对植物雌激素及其人体代谢产物进行了全面分析和效力比较，以研究它们在人细胞中与ER的结合、诱导/抑制ERα和ERβ反式激活以及共激活因子募集情况。大豆来源的染料木黄酮、香豆雌酚和雌马酚相比于ERα更倾向于反式激活ERβ，且效力比己烯雌酚低10至100倍。相比之下，玉米赤霉烯酮是所测试的最有效的植物雌激素，且优先激活ERα。所测试的所有其他植物雌激素，包括白藜芦醇、大豆苷元的人体代谢产物和肠内酯，都是弱ER激动剂。有趣的是，大豆苷元代谢产物3',4',7-异黄酮和4',6,7-异黄酮是ERα和ERβ的超级激动剂。与一致的雌激素反应元件相比，在雌激素反应性C3启动子上，所有测试的植物雌激素与己烯雌酚相比激活ERα和ERβ的效力均降低，表明存在一定程度的启动子依赖性。高剂量时，玉米赤霉烯酮和白藜芦醇对ERα和ERβ均具有拮抗作用。植物雌激素与17β-雌二醇相似，优先增强GRIP1与ERα的募集。相比之下，对于ERβ，未明显表现出对一种共激活因子（GRIP1或SRC-1）的偏好，且总体共激活因子结合不如ERα明显。由于大豆来源的异黄酮、香豆雌酚、白藜芦醇和玉米赤霉烯酮的含量及其（抗）雌激素效力，它们似乎有可能有效地充当内分泌干扰物。
