INVIVO EVIDENCE AGAINST THE EXISTENCE OF ANTIPROGESTINS DISRUPTING RECEPTOR-BINDING TO DNA

The binding of a steroid hormone to its receptor elicits a sequence Of events: activation of the receptor (probably through dissociation fro m a complex of heat shock proteins), dimerization, binding to hormone responsive elements, and finally modulation of gene transcription. RU 486, the first antiprogestin studied, has been shown to act at the las t step of this sequence: provoking an inefficient binding of the recep tor to hormone responsive elements. Recently, based on in vitro studie s, it has been proposed that ZK 98299 was the prototype of a second cl ass of antiprogestins that were supposed to act through disruption of the binding to DNA. We have devised methods allowing us to study the v arious steps of agonist or antagonist action in vivo. We show here tha t RU 486 and ZK 98299 have the same effects on receptor activation, di merization, and binding to hormone responsive elements; differences in their action are explained by the 10-fold difference in their affinit y for the receptor (ZK 98299 having the lower affinity).