INDUCTION OF RAT HEPATIC GLUCOCORTICOID-INDUCIBLE CYTOCHROME-P450 3A BY METYRAPONE

The bipyridyl compound metyrapone is a potent inhibitor of cytochromes P450, a gene superfamily of haemoproteins involved in the metabolism of many xenobiotics as well as endogenous compounds such as steroid ho rmones. Administration of metyrapone to male rats induces the expressi on of the cytochrome P450 sub-family 3A (CYP3A). In order to determine whether metyrapone was causing the induction of CYP3A by blocking end ogenous glucocorticoid metabolism, CYP3A levels were examined in rat h epatocytes cultured in serum-free medium supplemented with hydrocortis one 21-hemisuccinate plus or minus metyrapone. Western blotting indica ted that metyrapone alone induces CYP3A and that hydrocortisone 21-hem isuccinate is ineffective. However, hydrocortisone 21 -hemisuccinate e nhanced the levels of CYP3A induced by metyrapone. In contrast, glucoc orticoid-inducible tyrosine aminotransferase (TAT) activity was unaffe cted by metyrapone but metyrapone enhanced the levels induced by hydro cortisone 21-hemisuccinate. An examination of the metabolism of hydroc ortisone by rat hepatocytes in vitro indicated that metyrapone perturb ed the catabolism of hydrocortisone under conditions which give rise t o an enhancement of hydrocortisone 21-hemisuccinate and hydrocortisone -dependent TAT induction. However, evidence is presented to suggest th at such a perturbation of hydrocortisone metabolism could not account for the glucocorticoid potency amplifying property of metyrapone. Thus the induction of CYP3A and the enhancement of glucocorticoid-mediated TAT induction appears not to be associated with any perturbation in g lucocorticoid metabolism but with some other as yet undefined mechanis m(s).