Inhibition of 3-methylindole bioactivation by the cytochrome P-450 suicide substrates 1-aminobenzotriazole and alpha-methylbenzylaminobenzotriazole.
The cytochrome P-450 suicide substrates 1-aminobenzotriazole (ABT) and alpha-methylbenzylaminobenzotriazole (alpha MB) were used as probes to examine the participation of cytochrome P-450 monooxygenases in the metabolism and covalent binding of 3-methylindole. ABT was a potent inactivator of 3-methylindole turnover and covalent binding of [methyl-14C]3-methylindole to protein in goat lung microsomal incubations. Both covalent binding and 3-methylindole turnover were decreased approximately 50% at 0.01 mM and 100% at 0.1 mM concentrations of ABT. The effects of ABT indicated that toxicity, as related to covalent binding, was directly dependent upon cytochrome P-450 catalysis. The inactivation of 3-methylindole turnover was greater with a 0.01 mM concentration of the isozyme-selective inhibitor alpha MB, 74% as compared with 47% for ABT. alpha MB (0.01 mM) decreased benzphetamine N-demethylase activity by 82% but decreased 7-ethoxyresorufin O-deethylase activity by only 28%. Thus, both 3-methylindole metabolism and benzphetamine oxidation were selectively inactivated by alpha MB. These findings suggest that 3-methylindole is metabolized to alkylating, electrophilic intermediates preferentially by the homologues of "phenobarbital-inducible" isozymes (presumably forms 2 and 5 in analogy to rabbit lung isozymes) to cytochrome P-450 in pulmonary microsomes, rather than by the polycyclic aromatic hydrocarbon-inducible isozymes.
Huijzer
J C
JC
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Adams
J D
JD
Jaw
J Y
JY
Yost
G S
GS
D000818:Animals; D001711:Biotransformation / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006041:Goats; D007211:Indoles / Q000493:pharmacokinetics*; D012862:Skatole / Q000493:pharmacokinetics* / Q000633:toxicity; D014230:Triazoles / Q000494:pharmacology*
D007211:Indoles; D014230:Triazoles; C059849:alpha-methylbenzylaminobenzotriazole; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System; D012862:Skatole