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 a and b (ERa and ERb). Resveratrol, trans-3,5,49-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 ERa vs. ERb in this binding is unknown. Here we report that resveratrol binds ERb and ERa with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERb with higher affinity than ERa. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERa or ERb. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERb has higher transcriptional activity than E2-liganded ERb at a single palindromic ERE. This indicates that those tissues that uniquely express ERb or that express higher levels of ERb than ERa 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 E2. We report that resveratrol exhibits E2 antagonist activity for ERa with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERb. These data indicate that resveratrol differentially affects the transcriptional activity of ERa and ERb in an ERE sequence-dependent manner. (Endocrinology 141: 3657–3667, 2000) R is a bioflavonoid found naturally in grapes that has both chemopreventive (1–3) and cardioprotective activities (4) in vitro and in animal models. Red wine that contains 1–10 mg/liter and can be a major dietary source of resveratrol (5). Studies on the bioavailability of resveratrol in rats lead to the conclusion that even an average consumer of red wine, particularly over the long term, can absorb quantities of resveratrol that correlate with the beneficial health effects of red wine consumption observed in epidemiological studies (6–8). Resveratrol is a stilbene that exists as cisand trans-isomers. The trans-isomer appears to have greater anticancer and cardio-protective properties than the cis-isomer (9). Resveratrol has been characterized as a phytoestrogen based on its ability to bind to and activate estrogen receptor (ER) (10). ER is a nuclear steroid receptor that binds estrogens and regulates the transcription of estrogen-responsive genes by either binding directly to DNA, at particular sequences called estrogen response elements (EREs), or by interacting with other transcription factors, e.g. Sp1 (11), bound to their cognate sites on DNA. When activated by an agonist ligand, ERa interacts with coactivators, e.g. SRC-1 and CBP, that either acetylate lysine residues in histones to alter chromatin conformation and/or interact with components of the RNA polymerase II initiation complex to enhance target gene tran-