Age-related alteration in the activities of drug-metabolizing enzymes and contents of sex-specific forms of cytochrome P-450 in liver microsomes from male and female rats

Age-related changes in the amounts of sex-specific forms of cytochrome P-450 as well as the activities of drug-metabolizing enzymes in liver microsomes of Fischer-344 rats of different ages ranging from 3 to 30 months were studied. Activities of 7-propoxycoumarin O-depropylase and benzo(a)pyrene hydroxylase in male rats, which were higher than those in female rats in younger adults (3-12 months), decreased with increasing age, resulting in the loss of sex differences after 25 months. The male-specific form of cytochrome P-450, namely P-450-male, present in younger adults, was not detectable in older ages. In old male rats, the female-specific form of cytochrome P-450, namely P-450-female, appeared instead of P-450-male. In liver microsomes of young and old female rats, rather constant levels of P-450-female were observed, whereas P-450-male was not detectable. Serum concentrations of testosterone and estradiol were also quantitated. The ratio of testosterone to estradiol concentrations decreased with age in male rats whereas the ratio was not changed in female rats. Based on these results, we propose that the age-related decrease in the activities of drug-metabolizing enzymes in male rats is attributable to the change in the population of cytochrome P-450, especially P-450-male and P-450-female, probably owing to the alteration of the levels of gonadal hormones.