INDUCTION OF CYTOCHROME P4503A BY THE ANTIGLUCOCORTICOID MIFEPRISTONEAND A NOVEL HYPOCHOLESTEROLEMIC DRUG

Rat liver microsomal testosterone (250 mu M) hydroxylation and immunor eactive CYP3A protein were compared after administration of the antigl ucocorticoid RU 486 (50 mg.kg(-1).day(-1) for 4 days) and the hypochol esterolaemic drug SR-12813 (150 mg.kg(-1).day(-1) for 4 days), Markers of CYP3A-mediated enzyme activity (testosterone 15 beta-, 6 beta-, an d 2 beta-hydroxylation) were increased after administration of both dr ugs. Testosterone 6 beta-hydroxylation was increased 5-fold by RU 486 and 9-fold by SR-12813, Administration of dexamethasone alone at 150 m g.kg(-1).day(-1) or in combination with RU 486 induced testosterone 6 beta-hydroxylation 15- to 20-fold. The lack of antagonistic effect of RU 486 on dexamethasone-mediated CYP3A induction strengthens support f or the hypothesis that the ''classical glucocorticoid receptor'' does not play a part in this process. The induction of CYP3A enzymes by the bisphosphonate SR-12813 suggests the existence of a new class of comp ounds with CYP3A inducing properties.