Comparative Effects of R- and S-equol and Implication of Transactivation Functions (AF-1 and AF-2) in Estrogen Receptor-Induced Transcriptional Activity

Equol, one of the main metabolites of daidzein, is a chiral compound with pleiotropic effects on cellular signaling. This property may induce activation/ inhibition of the estrogen receptors (ER) alpha or beta, and therefore, explain the beneficial/ deleterious effects of equol on estrogen-dependent diseases. With its asymmetric centre at position C-3, equol can exist in two enantiomeric forms (R- and S-equol). To elucidate the yet unclear mechanisms of ER activation/inhibition by equol, we performed a comprehensive analysis of ER alpha and ER beta transactivation by racemic equol, as well as by enantiomerically pure forms. Racemic equol was prepared by catalytic hydrogenation from daidzein and separated into enantiomers by chiral HPLC. The configuration assignment was performed by optical rotatory power measurements. The ER-induced transactivation by R- and S-equol (0.1-10 mu M) and 17 beta-estradiol (E2, 10 nM) was studied using transient transfections of ER alpha and ER beta in CHO, HepG2 and HeLa cell lines. R- and S-equol induce ER transactivation in an opposite fashion according to the cellular context. R-equol and S-equol are more potent in inducing ER alpha in an AF-2 and AF-1 permissive cell line, respectively. Involvement of ER alpha transactivation functions (AF-1 and AF-2) in these effects has been examined. Both AF-1 and AF-2 are involved in racemic equol, R-equol and S-equol induced ER. transcriptional activity. These results could be of interest to find a specific ligand modulating ER transactivation and could contribute to explaining the diversity of equol actions in vivo.