Inhibition of 3-methylindole bioactivation by the cytochrome P-450 suicide substrates 1-aminobenzotriazole and alpha-methylbenzylaminobenzotriazole.
Inhibition of 3-methylindole bioactivation by the cytochrome P-450 suicide substrates 1-aminobenzotriazole and alpha-methylbenzylaminobenzotriazole.
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发表时间：
1989
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通讯作者：
J. Huijzer;J. Adams;J. Jaw;G. Yost
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作者：
J. Huijzer;J. Adams;J. Jaw;G. Yost
以细胞色素P-450自杀底物1-氨基苯并三唑（ABT）和α-甲基苄基氨基苯并三唑（α MB）为探针，研究了细胞色素P-450单加氧酶参与3-甲基吲哚的代谢和共价结合。ABT是山羊肺微粒体孵育中3-甲基吲哚周转和[甲基-14 C]3-甲基吲哚与蛋白质共价结合的有效灭活剂。共价结合和3-甲基吲哚营业额下降约50%，在0.01 mM和100%，在0.1 mM浓度的ABT。ABT的作用表明，与共价结合相关的毒性直接取决于细胞色素P-450的催化作用。3-甲基吲哚营业额的失活是更大的0.01 mM浓度的同工酶选择性抑制剂α MB，74%相比，ABT的47%。α MB（0.01 mM）使苄非他明N-脱甲基酶活性降低82%，但使7-乙氧基试卤灵O-脱乙基酶活性仅降低28%。因此，3-甲基吲哚代谢和苄非他明氧化都被α MB选择性灭活。这些研究结果表明，3-甲基吲哚代谢为烷基化，亲电中间体优先由同系物的“苯巴比妥诱导”同工酶（大概形式2和5类似于兔肺同工酶），细胞色素P-450在肺微粒体，而不是由多环芳烃诱导的同工酶。
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.