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  • Title: Isozyme-specific monoclonal antibody-directed assessment of induction of hepatic cytochrome p-450 by clotrimazole.
    Author: Khan WA, Kuhn C, Merk HF, Park SS, Gelboin HV, Bickers DR, Mukhtar H.
    Journal: Drug Metab Dispos; 1989; 17(4):360-4. PubMed ID: 2571472.
    Abstract:
    Clotrimazole, an N-substituted imidazole widely used as an antifungal agent, has been shown to both inhibit and induce hepatic cytochrome P-450 and related monooxygenase activities. In this study the profile of hepatic cytochrome P-450 isozyme(s) induced by clotrimazole treatment of male Sprague-Dawley rats was investigated. Clotrimazole administration (100 mg/kg, daily for 4 days, ig) resulted in 86% induction of spectrally detectable cytochrome P-450 in hepatic microsomes. In these microsomes 7-ethoxycoumarin O-deethylase (126%), aminopyrine N-demethylase (176%), benzphetamine N-demethylase (117%), p-nitrophenol hydroxylase (89%), and 7-ethoxyresorufin O-deethylase (62%) activities were significantly induced, whereas aryl hydrocarbon hydroxylase activity remained unchanged. Characterization of cytochrome P-450 isozyme(s) in hepatic microsomes prepared from clotrimazole-treated animals was based on the immunoreactivity of these microsomes with highly specific monoclonal antibodies (MAbs) raised against 3-methylcholanthrene-specific P-450 (MAb 1-7-1), phenobarbital-specific P-450 (MAb 2-66-3), pregnenolone-16 alpha-carbonitrile-specific P-450 (MAb C2), and ethanol-inducible P-450 (MAb 1-98-1). Western blot analysis of hepatic microsomes prepared from clotrimazole-treated animals with MAb 2-66-3, MAb 1-98-1, and MAb C2 revealed strong immunoreactive bands, whereas moderate reactivity was observed with MAb 1-7-1. MAb 2-66-3 significantly inhibited 7-ethoxycoumarin O-deethylase activity 45%), whereas MAb 1-7-1 moderately inhibited 7-ethoxyresorufin O-deethylase activity (-30%) in clotrimazole-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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