INACTIVATION OF ADRENAL CYTOCHROMES P450 BY 1-AMINOBENZOTRIAZOLE - DIVERGENCE OF IN-VIVO AND IN-VITRO ACTIONS

Recent investigations demonstrated that administration of 1-aminobenzo triazole (ABT) to rats caused adrenal gland enlargement. Studies were done to pursue the mechanism(s) involved. Preliminary experiments reve aled that the adrenal enlargement caused by ABT was associated with a decline in plasma corticosterone concentrations, suggesting inhibition of adrenal steroidogenesis. Indeed, a single injection of ABT (25 or 50 mg/kg body weight) to rats caused concentration-dependent declines (60-80%) in adrenal mitochondrial and microsomal cytochrome P450 (P450 ) concentrations. The decreases in adrenal P450 levels exceeded those in hepatic microsomes. Accompanying the declines in adrenal P450 conce ntrations were decreases in steroid hydroxylase activities. Mitochondr ial 11 beta- hydroxylase and cholesterol side-chain cleavage activitie s and microsomal 21-hydroxylase activity were diminished markedly (60- 90%) by ABT treatment. In contrast, activity of adrenal 3 beta-hydroxy steroid dehydrogenase-isomerase was not affected by ABT, indicating sp ecificity for P450-dependent reactions. Incubation of adrenal microsom es or mitochondria in vitro with ABT plus an NADPH-generating system h ad no effect on P450 concentrations or on steroid hydroxylase activiti es. Similar incubations with hepatic microsomes caused declines in P45 0 levels and in the rates of P450-mediated xenobiotic metabolism. The results demonstrate that ABT is a potent inhibitor of adrenal steroid hydroxylases in vivo, but the in vitro studies indicate that the mecha nism of action differs from that on other P450 isozymes. The absence o f inhibitor effects in vitro suggests that an extra-adrenal metabolite of ABT is responsible for the in vivo inactivation of steroidogenic e nzymes.