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© 1992 Oxford University Press

research-article

1-Aminobenzotriazole-Induced Destruction of Hepatic and Renal Cytochromes P450 in Male Sprague-Dawley Rats1

CHERYL A. MUGFORD*, MILDRED MORTILLO{dagger}, BRUCE A. MICO{dagger} and JOAN B. TARLOFF2

*Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science Hoffman-Roche Incorporated {dagger}Department of Drug Metabolism Hoffman-Roche Incorporated

Received September 3, 1991; accepted November 25, 1991

1-Aminobenzotriazole (ABT) is a suicide substrate of both hepatic and pulmonary cytochromes P450. The present studies were designed to compare the effects of ABT on hepatic and renal metabolism. Hepatic and renal microsomes and cytosol were prepared from male Sprague-Dawley rats following ABT pretreatment (0–100 mg/kg ip) for various times. Administration of 100 mg ABT/kg produced profound reductions in P450 content in both liver and kidney within 2 hr; loss of P450 in both tissues persisted for at least 48 hours. ABT-induced destruction of P450 was dose-dependent. Maximal destruction of about 80% of total hepatic P450 occurred at dosages of ABT equal to or greater than 10 mg/kg. Maximal destruction of about 80% of total renal P450 occurred at dosages of ABT equal to or greater than 50 mg/kg. In vitro, ABT rapidly and efficiently destroyed P450 in both hepatic and renal microsomes prepared from naive male Sprague-Dawley rats. Incubation of hepatic or renal microsomes in vitro with ABT produced detectable destruction of P450 within 5 min. Maximal destruction of P450 occurred within 10 min in both hepatic and renal microsomes during in vitro incubation with ABT. ABT-induced destruction of P450 in vitro was concentration-dependent. For hepatic microsomes, maximal destruction of about 70% of P450 required concentrations of ABT equal to or greater than 10 mM. For renal microsomes, maximal destruction of about 80% of P450 required concentrations of ABT equal to or greater than 10 mM. In both liver and kidney, only P450 content and P450-dependent activities were significantly decreased. Cytochrome b5, NADPH cytochrome c reductase, glutathione S-transferase, glucuronyl transferase, and reduced glutathione contents were unaltered. These data suggest that ABT selectively and effectively destroys both hepatic and renal P450. ABT may be a useful tool to probe the potential role of P450 in the bioactivation of certain compounds.


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