In Vitro Inhibitory Effect of 1-Aminobenzotriazole on Drug Oxidations Catalyzed by Human Cytochrome P450 Enzymes: A Comparison with SKF-525A and Ketoconazole

doi:10.2133/dmpk.18.287

Drug Metabolism and Pharmacokinetics

Volume 18, Issue 5, 2003, Pages 287-295

https://doi.org/10.2133/dmpk.18.287 Get rights and content

Summary:

1-Aminobenzotriazole (ABT) is widely used as a non-specific inhibitor of animal cytochrome P450 (CYP). In the present study, the inhibitory effect of ABT was investigated on drug oxidations catalyzed by human CYP isoforms. This inhibitory effect was compared with that of SKF-525A, another non-specific inhibitor, and ketoconazole, a potent inhibitor of CYP3A. Bacurovirus-expressed recombinant human CYP isoforms were used as an enzyme source. The specific activities for human CYP isoforms are: phenacetin O-deethylation, for CYP1A2; diclofenac 4′-hydroxylation, for CYP2C9; S-mephenytoin 4′-hydroxylation, for CYP2C19; bufuralol 1′-hydroxylation, for CYP2D6; chlorzoxazone 6-hydroxylation, for CYP2E1; testosterone 6β-hydroxylation, nifedipine oxidation, and midazolam 1′-hydroxylation, for CYP3A4. ABT inhibited both CYP1A2-dependent activity (Ki = 330 μM) and CYP2E1-dependent activity (Ki = 8.7 μM). In contrast, SKF-525A weakly inhibited CYP1A2-dependent activities (46% inhibition at 1200 μM) and CYP2E1-dependent activities (65% inhibition at 1000 μM). ABT exhibited the highest Ki value for CYP2C9-dependent diclofenac 4′-hydroxylation among those determined by this assay (Ki = 3500 μM). Moreover, SKF-525A showed strong inhibition of CYP2D6-dependent bufuralol 1′-hydroxylation (Ki = 0.043 μM). Ketoconazole inhibited all tested drug oxidations, however, its inhibitory effect on CYP1A2-dependent activities was very weak (50% inhibition at 120 μM). ABT, SKF-525A, and ketoconazole showed different selectivity and had a wide range of Ki values for the drug oxidations catalyzed by human CYP enzymes. Therefore, we conclude that inhibitory studies designed to predict the contribution of CYP enzymes to the metabolism of certain compounds should be performed using multiple CYP inhibitors, such as ABT, SKF-525A, and ketoconazole.

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Citation Excerpt :
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Regular ArticleIn Vitro Inhibitory Effect of 1-Aminobenzotriazole on Drug Oxidations Catalyzed by Human Cytochrome P450 Enzymes: A Comparison with SKF-525A and Ketoconazole

Summary:

Fundam. Appl. Toxicol.

Tetrahedron

Jpn. J. Pharmacol.

Biochem. Pharmacol.

J. Pharm. Sci.

Reactions and significance of cytochrome P-450 enzymes

J. Biol. Chem.

Extrahepatic metabolism of drugs in humans

Clin. Pharmacokinet.

Clinical importance of hepatic cytochrome P450 in drug metabolism

Drug Metab. Rev.

Autocatalytic alkylation of the cytochrome P-450 prosthetic haem group by 1-aminobenzotriazole

Biochem. J.

Inactivation of rabbit pulmonary cytochrome P-450 in microsomes and isolated perfused lungs by the suicide substrate 1-aminobenzotriazole

J. Pharmacol. Exp. Ther.