Several synthetic chemicals inhibit progesterone receptor-mediated transactivation in yeast

The human progesterone receptor (hPR) B-form and a progesterone-sensitive reporter were expressed in yeast and used to screen a library of synthetic chemicals for their ability to function as agonists or antagonists of hPR. The transcriptional activity of hPR was not increased in the presence of over 40 individual chemicals. Seven chemicals decreased progesterone-dependent activity in yeast. The most effective chemicals were 6-hydroxychrysene, 1-hydroxypyrene, 4-hydroxy, 2',4',6'-trichloro biphenyl, and 4-hydroxy, 2',3',4',5'-tetrachloro biphenyl. The decrease of progesterone-mediated transactivation strongly correlated with their displacement of [H-3]progesterone from hPR. The absence of the hydroxyl group on the above chemicals completely abolished their inhibitory activity. The other chemicals which decreased progesterone activity were endosulfan II, endosulfan sulfate, and lindane. These chemicals did not inhibit [H-3]progesterone binding, suggesting that they inhibit progesterone action by interacting with a region of hPR distinct from binding [H-3]progesterone or by a mechanism independent of hPR. These results highlight the utility of yeast for screening hormonally-active chemicals. In addition, hydroxylation appears to be essential for the interaction of some chemicals with hPR. (C) 1997 Academic Press.