A mechanism of age-associated alterations in plasma
sex hormone levels as well as their effect on
drug metabolizing
enzyme activities were studied using male and female Fischer 344 rats of ages ranging between 3 and 30 months. Plasma
testosterone levels as well as the activity of the rate limiting
enzyme required for
testosterone production in testes,
androstenedione 17 beta-oxido-
reductase, decreased with senescence in parallel with the alteration of
drug metabolism whereas activity of hepatic microsomal
androstenedione 5 alpha-reductase, the
testosterone metabolizing
enzyme, increased with age. The profile of
drug metabolizing activities with
imipramine,
diazepam,
hexobarbital,
lidocaine,
p-nitroanisole and
androstenedione as substrates in old (27-month-old) male rats was almost identical to that in young or old female rats, indicating that neonatal androgenic imprinting of
drug metabolism in male rats was erased in senescence.
Castration of adult (9-month-old) male rats caused a decrease in
drug metabolism, but did not result in complete
feminization of the profiles of
drug metabolism as was observed in old male rats, indicating that neonatally imprinted male pattern of
drug metabolism was still retained in the absence of
testosterone in adult male rats.
Testosterone administration restored completely male-level activities in castrated adult rats, but caused only a partial recovery in old male rats. It is proposed that senescence associated
feminization of the
drug-metabolizing ability of the male rat liver may be in part due to the decrease in
testosterone levels in old age and in part to the loss of neonatal imprinting.