Effect of aging on drug-metabolizing enzymes important in acetaminophen elimination

Abstract

The effects of aging on selected drug-metabolizing enzyme activities, the pattern of phenol and bile salt sulfotransferase isoenzymes and the pharmacokinetics of acetaminophen were examined in male Fischer 344 rats at ages 5, 14 and 25 months. Aging decreased sulfotransferase activity toward acetaminophen while activity toward glycolithocholate increased with age. Glucuronosyltransferase activity toward estrone increased with age, while activity toward testosterone, morphine and naphthol remained constant. Glutathione-S-transferase (1-chloro-2,4-dinitrobenzene) activity was also unchanged through the various age groups. Cytochrome P-450 content and monooxygenase activity (p-nitroanisole demethylation) activity decreased with advancing age. Overall, the age-related in vitro changes in enzyme activities approached or equaled values measured in 5-month-old female Fischer 344 rats. Moreover, age-related alterations in total phenol sulfotransferase activity and the isozyme pattern paralleled changes in the in vivo elimination kinetics and metabolic fate of acetaminophen. The fraction of drug excreted as the sulfate conjugate and the partial clearance to acetaminophen sulfate decreased with increasing age. Conversely, the fraction excreted as the glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. There was no effect of aging on the total clearance of acetaminophen. The gender-related differences in the pattern of sulfotransferase isozyme activity toward phenolic and bile salt acceptors disappeared with age. Age-related changes in sulfation and perhaps glucuronidation in male rats appear to feminize hepatic biotransformation and may arise due to altered gonadal hormone status.