Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta

Epidemiological evidence indicates that phytoestrogens inhibit cancer forma tion and growth, reduce cholesterol levels, and show benefits in treating o steoporosis. At least some of these activities are mediated through the int eraction of phytoestrogens with estrogen receptors alpha and beta (ER alpha and ER beta). Resveratrol, trans-3,5,4'-trihydroxystilbene, is a phytoestr ogen in grapes that is present in red wine. Resveratrol was shown to bind E R 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 re sveratrol binds ER beta and ER alpha with comparable affinity, but with 7,0 00-fold lower affinity than estradiol (E-2). Thus, resveratrol differs from other phytoestrogens that bind ERP with higher affinity than ER alpha. Res veratrol acts as an estrogen agonist and stimulates ERE-driven reporter gen e activity in CHO-K1 cells expressing either ER alpha or ER beta. The estro gen agonist activity of resveratrol depends on the ERE sequence and the typ e of ER. Resveratrol-liganded ER beta has higher transcriptional activity t han E-2-liganded ER beta at a single palindromic ERE. This indicates that t hose 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 agon ist activity. For the natural, imperfect EREs from the human c-fos, pS2, an d progesterone receptor (PR) genes, resveratrol shows activity comparable t o that induced by E-2. We report that resveratrol exhibits E-2 antagonist a ctivity for ER alpha with select EREs. in contrast, resveratrol shows no E- 2 antagonist activity with ER beta. These data indicate that resveratrol di fferentially affects the transcriptional activity of ER alpha and ER beta i n an ERE sequence-dependent manner.