Alteration of Plasma Sex Hormone Levels Associated with Old Age and Its Effect on Hepatic Drug Metabolism in Rats

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.