D. Xu et al., INHIBITION OF ADRENAL-STEROID METABOLISM BY ADMINISTRATION OF 1-AMINOBENZOTRIAZOLE TO GUINEA-PIGS, Journal of steroid biochemistry and molecular biology, 54(5-6), 1995, pp. 281-285
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.