A comparison of the effects of benzpyrene administration on some hepatic microsomal mixed-function oxidases of rats and mice

Abstract

There were marked differences in the responses of the hepatic microsomal enzymes of rats and mice after treatment of these animals with benzpyrene. Benzpyrene treatment caused qualitative as well as quantitative changes in the hepatic microsomal mixed-function oxidases of rats. Qualitative changes included: a decrease in the ratio of the peaks at 430 and 455 mμ in the pH-dependent ethyl isocyanide difference spectrum; an increase in the pH optimum of aniline p-hydroxylation; and changes in the apparent Michaelis-Menten kinetics of aniline, (+)-benzphetamine and benzpyrene metabolism. In addition, there were marked alterations in the substrate concentration-dependent “kinetics” of the difference spectra produced by the interaction of aniline and (+)-benzphetamine with rat liver microsomal P-450. Treatment of rats with benzpyrene increased both the apparent V max and apparent K m of aniline p-hydroxylation, and the degree of change was dependent upon substrate concentration and pH of the incubation systems. Benzpyrene treatment also increased the apparent ΔA max of the aniline-induced microsomal difference spectrum, although the apparent spectral dissociation constant ( K s ) was decreased. Both the rate of (+)-benzphetamine metabolism and the magnitude of the (+)-benzphetamine-induced microsomal difference spectrum were decreased after benzpyrene treatment. Treatment of rats with benzpyrene also increased the apparent V max and decreased the apparent K m of benzpyrene hydroxylation several-fold. In identical experiments performed concomitantly with mice, benzpyrene treatment produced no measurable effect on any of these characteristics of the mouse hepatic microsomal mixed-function oxidases, except for a decrease in the magnitude of the (+)-benzphetamine-induced microsomal difference spectrum. Although the administration of benzpyrene produced no stimulatory effects on the drug-metabolizing enzymes of the mouse, treatment with 3-methylcholanthrene did enhance the benzpyrene hydroxylase activity of mouse liver microsomes. Studies showed that the apparent V max of this reaction was increased more than 2-fold.