INHIBITION OF ADRENAL-STEROID METABOLISM BY ADMINISTRATION OF 1-AMINOBENZOTRIAZOLE TO GUINEA-PIGS

Prior in vitro investigations demonstrated that the P450 suicide subst rate, 1-aminobenzotriazole (ABT), was a potent inhibitor of xenobiotic metabolism but had no effect on steroidogenic enzymes in the guinea p ig adrenal cortex. Studies were done to determine if ABT administratio n to guinea pigs in vivo also selectively inhibited adrenal xenobiotic metabolism. At single doses of 25 or 50 mg/kg, ABT effected rapid dec reases in spectrally detectable adrenal P450 concentrations. The highe r dose caused approx. 75% decreases in microsomal and mitochondrial P4 50 levels within 2 h. The decreases in P450 were sustained for 24 h bu t concentrations returned to control levels within 72 h. Accompanying the APT-induced decreases in adrenal P450 content were proportionately similar decreases in P450-mediated xenobiotic and steroid metabolism. Microsomal benzo(a)pyrene hydroxylase, benzphetamine N-demethylase, 1 7 alpha-hydroxylase and 21-hydroxylase activities were decreased to 20 -25% of control values by the higher dose of ABT. Mitochondrial 11 bet a-hydroxylase and cholesterol sidechain cleavage activities were simil arly diminished by ABT treatment. Adrenal 3 beta-hydroxysteroid dehydr ogenase activity, by contrast, was not affected by ABT, indicating spe cificity for P450-catalyzed reactions. The results demonstrate that AB T in vivo is a non-selective inhibitor of adrenal steroid- and xenobio tic-metabolizing P450 isozymes. The absence of ABT effects on steroid metabolism in vitro suggests that an extra-adrenal metabolite may medi ate the in vivo inhibition of steroidogenesis.