The profiles of hepatic
drug metabolism were obtained by using young and old male and female rats. The profile obtained from old male rats was completely different from that from young male rats, while it was almost identical to those of females of any ages. This was due to the selective decrease in male hepatic
enzyme activities showing higher activities than females to the activity levels of females which did not alter much with aging.
Castration of young adult male rats caused a decrease in
enzyme activities but did not result in the
feminization of the metabolic profile. Administration of
testosterone to old male rats resulted in the recovery of the profile of young male rats, but the levels of activities were not as high as young male rats. Plasma
testosterone levels were found to decrease in parallel with
drug metabolizing activities of male rats during aging. These results suggest that
sex hormones play important roles in the alteration of
drug metabolizing activities in male rats with aging. The loss of male characteristics in profile of
drug metabolism during aging was evaluated by use of antibody to the male specific
cytochrome P-450, P-450 m1. Anti-P-450 ml strongly inhibited
imipramine N-demethylase activity, which showed marked sex (male greater than female) and age (young greater than old) differences, while this did not inhibit
imipramine 2-hydroxylase activity, which showed no sex or age differences. The portion of
N-demethylase activity inhibited by this antibody decreased in old rats while the portion not inhibited did not decrease with age. These results indicate that the decrease of sex specific
cytochrome P-450 is responsible for the age-associated decrease in at least one of the
drug metabolizing
enzyme activities in male rats. It is suggested that some processes of the control mechanism of the gene expression of male specific
cytochrome P-450 may be altered with old age.