Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug.

Rat liver microsomal testosterone (250 microM) hydroxylation and immunoreactive CYP3A protein were compared after administration of the antiglucocorticoid RU 486 (50 mg.kg-1.day-1 for 4 days) and the hypocholesterolaemic drug SR-12813 (150 mg.kg-1.day-1 for 4 days). Markers of CYP3A-mediated enzyme activity (testosterone 15 beta-, 6 beta-, and 2 beta-hydroxylation) were increased after administration of both drugs. Testosterone 6 beta-hydroxylation was increased 5-fold by RU 486 and 9-fold by SR-12813. Administration of dexamethasone alone at 150 mg.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 for 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 compounds with CYP3A inducing properties.