Obstacles to the prediction of estrogenicity from chemical structure: Assay-mediated metabolic transformation and the apparent promiscuous nature of the estrogen receptor

Information on structure-activity relationships (SAR) and pathways of metab olic activation would facilitate the preliminary screening of chemicals for estrogenic potential. Published crystallographic studies of the estrogen r eceptor (ER) imply an essential role of the two hydroxyl groups on estradio l (17 beta-E-2) for its binding to ER. The influence of these hydroxyl grou ps on ER binding and estrogenicity was evaluated by the study of 17 beta-E- 2 with one or both of these hydroxyl groups removed (17 beta-desoxyestradio l and 3,17 beta-bisdesoxyestradiol, respectively). 6-Hydroxytetralin (17 be ta-E-2 with its C- and D-rings removed) and other synthetic estrogens were also studied. The estrogenicity assays comprised a yeast ER-mediated transc ription assay, mammalian cell transcription assays incorporating either ER alpha or ER beta, and the immature rat uterotrophic assay. With the excepti on of 6-hydroxytetralin in the uterotrophic assay, all the chemicals were a ctive in all the assays. Hydroxylation of the two desoxy compounds to estra diol was shown to occur in immature female rats, but metabolism was not imp licated in the responses observed in the ER-binding and yeast systems. It i s concluded that the 3-hydroxyl and 17 beta-hydroxyl groups of 17 beta-E-2 are not absolute requirements for estrogenicity. It would therefore be of v alue to the derivation of SAR for estrogenicity were the crystal structure of the bisdesoxy-E-2/ER complex to be evaluated. (C) 2000 Elsevier Science Inc.