Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β
Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β
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DOI：
10.1210/en.141.10.3657
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发表时间：
2000-10-01
期刊：
影响因子：
4.8
通讯作者：
Klinge, CM
中科院分区：
文献类型：
--
作者：
Bowers, JL;Tyulmenkov, VV;Klinge, CM
流行病学证据表明，植物雌激素抑制癌症的形成和生长，降低胆固醇水平，并显示出治疗骨质疏松症的益处。这些活性中的至少一些是通过植物雌激素与雌激素受体α和β（ER α和ER β）的相互作用介导的。白藜芦醇，反式-3，5，4 '-三羟基芪，是葡萄中的一种植物雌激素，存在于红酒中。白藜芦醇被证明可以结合MCF-7和大鼠子宫胞质提取物中的ER。然而，ER α与ER β在这种结合中的贡献是未知的。在这里，我们报告白藜芦醇与ER β和ER α的结合亲和力相当，但亲和力比雌二醇（E-2）低7，000倍。因此，白藜芦醇不同于其他植物雌激素，其结合ERP的亲和力高于ER α。白藜芦醇作为一种雌激素激动剂，刺激表达ER α或ER β的CHO-K1细胞中的ER驱动的报告基因活性。白藜芦醇的雌激素激动剂活性取决于ERE序列和ER的类型。白藜芦醇配体的ER β在单个回文ERE处具有比E-2配体的ER β更高的转录活性。这表明那些独特表达ER β或表达ER β水平高于ER α的组织可能对白藜芦醇的雌激素激动剂活性更敏感。对于来自人类c-fos、pS2和孕酮受体（PR）基因的天然的、不完美的ERE，白藜芦醇显示出与E-2诱导的活性相当的活性。我们报告说，白藜芦醇表现出E-2拮抗剂活性的ER α与选择的EREs。相反，白藜芦醇对ER β没有显示E-2拮抗活性。这些数据表明，白藜芦醇差异影响ER α和ER β的转录活性在一个ERE序列依赖性的方式。
Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors alpha and beta (ER alpha and ER beta). Resveratrol, trans-3,5,4'-trihydroxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ER alpha vs. ER beta in this binding is unknown. Here we report that resveratrol binds ER beta and ER alpha with comparable affinity, but with 7,000-fold lower affinity than estradiol (E-2). Thus, resveratrol differs from other phytoestrogens that bind ERP with higher affinity than ER alpha. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ER alpha or ER beta. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ER beta has higher transcriptional activity than E-2-liganded ER beta at a single palindromic ERE. This indicates that those tissues that uniquely express ER beta or that express higher levels of ER beta than ER alpha may be more sensitive to resveratrol's estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E-2. We report that resveratrol exhibits E-2 antagonist activity for ER alpha with select EREs. in contrast, resveratrol shows no E-2 antagonist activity with ER beta. These data indicate that resveratrol differentially affects the transcriptional activity of ER alpha and ER beta in an ERE sequence-dependent manner.