Dose-dependent, mechanism-based inactivation of cytochrome P450 monooxygenases in vivo by 1-aminobenzotriazole in liver, lung, and kidney of untreated, phenobarbital-treated, and β-naphthoflavone-treated guinea pigs

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  1. Get@NRC: Dose-dependent, mechanism-based inactivation of cytochrome P450 monooxygenases in vivo by 1-aminobenzotriazole in liver, lung, and kidney of untreated, phenobarbital-treated, and β-naphthoflavone-treated guinea pigs (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1139/y92-231
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TypeArticle
Journal titleCanadian Journal of Physiology and Pharmacology = Revue canadienne de physiologie et pharmacologie
ISSN0008-4212
1205-7541
Volume70
Issue12
Pages16101617
AbstractThe mechanism-based inactivation of the cytochrome P450 (P450) dependent monooxygenase system was studied in vivo in liver, lung, and kidney of untreated, phenobarbital-treated, and β-naphthoflavone-treated guinea pigs 24 h after administration of 1-aminobenzotriazole (1 – 100 mg/kg, i.p.). Microsomal isozyme-selective or -specific monooxygenase activities were inhibited in a dose-dependent manner in all three organs. In the liver of untreated and phenobarbital-treated animals, 7-pentoxyresorufin O-depentylation (catalyzed primarily by P450 2Bx, an orthologue of rabbit P450 2B4/rat 2B1) was inhibited more than 7-ethoxyresorufin O-deethylation (P450 1A1), 4-aminobiphenyl N-hydroxylation (P450 1A2), erythromycin N-demefhylation (P450 3A), or benzphetamine N-demethylation; in β-naphthoflavone-treated animals, 4-aminobiphenyl N-hydroxylation activity was preferentially inhibited. In lung, the order of inactivation of monooxygenase activities was 4-aminobiphenyl N-hydroxylation (4Bx, the orthologue of rabbit 4B1) > 7-pentoxyresorufin O-depentylation activity (2Bx) > 7-ethoxyresorufin O-deethylation (1A1; for example 72, 53, and 29% inactivation, respectively, in phenobarbital-treated animals at 100 mg/kg). In all three tissues the loss in spectrally assayed P450 content corresponds quite well to the inhibition of monooxygenase activities. Thus, these studies show that 1-aminobenzotriazole is an effective inactivator of the pulmonary, hepatic, and renal P450 systems in guinea pigs following i.p. administration, and that P450 1A2 (liver) and P450 4Bx (lung), isozymes efficient for the oxidation of primary aromatic amines, are preferentially inactivated.Key words: cytochrome P450, 1-aminobenzotriazole, mechanism-based inhibition, lung, liver.
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PublisherNational Research Council Canada Research Press
LanguageEnglish
AffiliationNational Research Council Canada
Peer reviewedYes
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NPARC number23000934
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Record identifier10fbdd7d-3ca2-4bc7-9777-341bcc6fc2a2
Record created2016-11-18
Record modified2016-11-18
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