Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β

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.