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

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 have been compared. The results establish that 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, however, as in 1-(2-isopropylphenyl)imidazole, significantly decreases both the Ki and alphaKi 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 have also been examined. The results establish that alpha-naphthoflavone is the most effective in vitro inhibitor. The results also indicate that the microsomal monooxygenase activities induced in rat liver by alpha-naphthoflavone, beta-naphthoflavone, and 3-methylcholanthrene are not equivalent. Based upon the observed results, it is concluded that 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.