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

1-Aminobenzotriazole (ABT) is a suicide substrate of both hepaticand pulmonary cytochromes P450. The present studies were designedto compare the effects of ABT on hepatic and renal metabolism.Hepatic and renal microsomes and cytosol were prepared frommale Sprague-Dawley rats following ABT pretreatment (0–100mg/kg ip) for various times. Administration of 100 mg ABT/kgproduced profound reductions in P450 content in both liver andkidney within 2 hr; loss of P450 in both tissues persisted forat least 48 hours. ABT-induced destruction of P450 was dose-dependent.Maximal destruction of about 80% of total hepatic P450 occurredat dosages of ABT equal to or greater than 10 mg/kg. Maximaldestruction of about 80% of total renal P450 occurred at dosagesof ABT equal to or greater than 50 mg/kg. In vitro, ABT rapidlyand efficiently destroyed P450 in both hepatic and renal microsomesprepared from naive male Sprague-Dawley rats. Incubation ofhepatic or renal microsomes in vitro with ABT produced detectabledestruction of P450 within 5 min. Maximal destruction of P450occurred within 10 min in both hepatic and renal microsomesduring in vitro incubation with ABT. ABT-induced destructionof P450 in vitro was concentration-dependent. For hepatic microsomes,maximal destruction of about 70% of P450 required concentrationsof ABT equal to or greater than 10 mM. For renal microsomes,maximal destruction of about 80% of P450 required concentrationsof ABT equal to or greater than 10 mM. In both liver and kidney,only P450 content and P450-dependent activities were significantlydecreased. Cytochrome b₅, NADPH cytochrome c reductase, glutathioneS-transferase, glucuronyl transferase, and reduced glutathionecontents were unaltered. These data suggest that ABT selectivelyand effectively destroys both hepatic and renal P450. ABT maybe a useful tool to probe the potential role of P450 in thebioactivation of certain compounds.