Regulation of hepatic monooxygenases by phenobarbital, 3-methylcholanthrene, and polychlorinated biphenyls in rapid and slow acetylator mice

A/J and C57BL/6J inbred mouse strains have been previously used as models of slow and fast acetylators, respectively, of human acetylator polymorphism. Studies were carried out to characterize possible differences in basal activities of hepatic monooxygenases and the response of these mouse strains to microsomal enzyme inducers. No significant difference in cytochrome P-450 content and associated enzyme activities of ethylmorphine N-demethylase and benzo(a)pyrene hydroxylase were observed between the two strains. The administration of the inducers, phenobarbital or the polychlorinated biphenyl mixture Aroclor 1254, resulted in significant increases in cytochrome P-450 and ethylmorphine N-demethylase activity and minimal changes in benzo(a)pyrene hydroxylase activity in both strains. Pretreatment with 3-methylcholanthrene resulted in little or no increase in N-demethylase activity in both strains. The polycyclic hydrocarbon caused a CO difference spectral shift to a lower wavelength only in the C57BL/6J mice. Further, it increased benzo(a)pyrene hydroxylase activity in both strains, but to a greater extent in the C57BL/6J strain. Electrophoretic studies using solubilized microsomal preparations confirmed the findings that the fast acetylators were highly responsive to the inducing properties of the polycyclic aromatic hydrocarbon, whereas the slow acetylators were relatively much less responsive to its inducing properties. The latter strain appeared to be more responsive to the inducing properties of the phenobarbital class of inducers, as reflected in the inducibility of cytochrome P-450 and the associated enzymic activities in the liver.