Abstract

The temporal aspect of the well known sex difference in drug metabolism in rats was studied by evaluating the drug-metabolizing system in liver preparations from animals that ranged in age from 21 to 56 days. The following observations were made. a) As male rats matured, N-demethylating activity generally increased in 9000g fractions from male rats, whereas decreases were seen in fractions from female rats. b) Rates of aniline hydroxylation declined with age and no sex difference was observed. A temporal increase in the degree of acetone enhancement of aniline hydroxylation was observed in males, but not in females. c) Changes in NADPH-cytochrome c and -neotetrazolium reductase. NADPH oxidase, and lipid peroxidase activities did not relate to changes in drug metabolism. d) Cytochrome P-450 levels of microsomes increased in males and remained constant in females, but the increase did not account for all of the increase in N-demethylating activity. e) Specific activities of cytochrome P-450, as related to N-demethylating activity, generally increased with age in males and decreased in females. f) The magnitude of the 430-nm maximum of the ethyl isocyanide spectrum increased with age with microsomes from males, but not from females. The pH at which the heights of the 430- and 455-nm peaks of the ethyl isocyanide difference spectrum were equal increased with age in males, but not in females. g) The apparent Michaelis constant for the N-demethylation of ethylmorphine decreased in males between the ages of 21 and 56 days, but remained unchanged in females. It is concluded a) that sex differences in drug metabolism observed in mature rats result not only from temporal increases in drug metabolism in males, but also from temporal decreases in females, and b) that these changes are due to qualitative changes in cytochrome P-450 in both males and females.