Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells.
Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells.
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发表时间：
2004
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通讯作者：
S. O. Mueller;S. Simon;K. Chae;M. Metzler;K. Korach
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作者：
S. O. Mueller;S. Simon;K. Chae;M. Metzler;K. Korach
植物雌激素在细胞信号传导中发挥多效作用，在雌激素依赖性疾病中显示出一些有益的作用。然而，由于雌激素受体erα或erβ的激活/抑制，这些化合物可能诱导或抑制雌激素的作用，因此，有可能破坏雌激素信号。我们对植物雌激素及其人体代谢物进行了全面的分析和效价比较，这些代谢物在人细胞中与内质网结合、诱导/抑制内质网α和内质网β的转激活以及辅激活因子的募集。大豆衍生的染料木黄酮、库米雌醇和雌马酚比erα更倾向于erβ的转激活，其效力比己烯雌酚低10- 100倍。相比之下，玉米赤霉烯酮是最有效的植物雌激素，并优先激活erα。所有其他的植物雌激素，包括白藜芦醇和大豆黄素和肠内酯的人体代谢物，都是弱内质网激动剂。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。所有的植物雌激素测试显示，与己烯雌酚相比，在雌激素应答的C3启动子上激活erα和erβ的能力降低，与雌激素应答元件相比，表明启动子依赖程度。玉米赤霉烯酮和白藜芦醇在高剂量时对erα和erβ均具有拮抗作用。与17 -雌二醇类似，植物雌激素优先增强GRIP1对er - α的募集。相比之下，erβ对一种共激活因子（GRIP1或SRC-1）没有明显的偏好，总体共激活因子的关联不如erα明显。由于它们的丰度和（抗）雌激素的能力，大豆衍生的异黄酮，库米雌醇，白藜芦醇和玉米赤霉酮似乎有可能有效地作为内分泌干扰物发挥作用。
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.