Effects of 1-arylpyrroles and naphthoflavones upon cytochrome P-450 dependent monooxygenase activities

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Abstract
The inhibitions of cytochrome P-450 dependent monooxygenase activity in microsomes from rat liver by 1-phenylpyrrole, 1-(2-isopropylphenyl)pyrrole, 4(5)-phenylimidazole and 1-(2-isopropylphenyl)imidazole were compared. The presence of an imidazole N-3 nitrogen substituent is not required to inhibit the monooxygenase activity measured by the deethylation of 7-ethoxycoumarin. The presence of an appropriately situated N-3 atom, as in 1-(2-isopropylphenyl)imidazole, significantly decreases the Ki [inhibition constant] and .alpha.Ki [.alpha.-phase Ki] of these mixed type inhibitors. The induction of 7-ethoxycoumarin deethylase activity in the microsomal fraction from rat liver by .alpha.-naphthoflavone, .beta.-naphthoflavone and 3-methylcholanthrene and the inhibition of these activities by flavone and .alpha.-, .beta.- and .gamma.-naphthoflavone were examined. .alpha.-Naphthoflavone is the most effective in vitro inhibitor. The microsomal monooxygenase activities induced in rat liver by .alpha.-naphthoflavone, .beta.-naphthoflavone and 3-methylcholanthrene are not equivalent. Differential effects of .alpha.- and .beta.-naphthoflavone on aryl hydrocarbon skin tumorigenesis may be the result of differential enzyme induction rather than the result of differential enzyme inhibition.