SEVERAL SYNTHETIC CHEMICALS INHIBIT PROGESTERONE RECEPTOR-MEDIATED TRANSACTIVATION IN YEAST

The human progesterone receptor (hPR) B-form and a progesterone-sensit ive reporter were expressed in yeast and used to screen a library of s ynthetic chemicals for their ability to function as agonists or antago nists of hPR. The transcriptional activity of hPR was not increased in the presence of over 40 individual chemicals. Seven chemicals decreas ed progesterone-dependent activity in yeast. The most effective chemic als were 6-hydroxychrysene, 1-hydroxypyrene, 4-hydroxy, 2',4',6'-trich loro biphenyl, and 4-hydroxy, 2',3',4',5'-tetrachloro biphenyl. The de crease of progesterone-mediated transactivation strongly correlated wi th their displacement of [H-3]progesterone from hPR. The absence of th e hydroxyl group on the above chemicals completely abolished their inh ibitory activity. The other chemicals which decreased progesterone act ivity were endosulfan II, endosulfan sulfate, and lindane. These chemi cals did not inhibit [H-3]progesterone binding, suggesting that they i nhibit progesterone action by interacting with a region of hPR distinc t 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 Pres s.