Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug
Williams, J. Andrew
Chenery, Richard J.
Hawksworth, Gabrielle M.
Rat liver microsomal testosterone (250μM) 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 15β-1 6β-, and 2β-hydroxylation) were increased after administration of both drugs. Testosterone 6β-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 6β-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.