Abstract

Significant declines occur in several in vitro indices of the liver microsomal cytochromes P-450-dependent drug-metabolizing system during aging in inbred male rats. However, several investigators have expressed serious reservations concerning the extrapolation of data derived from rodent models to humans. The few studies to evaluate the hepatic P-450-dependent drug-metabolizing system in young and old primates found no age-related declines in in vitro indices. The present study was designed to characterize the important hepatic microsomal drug-metabolizing enzyme, NADPH-cytochrome c (P-450) reductase (EC 1.6.2.4), as a function of aging in the rhesus monkey (Macaque mulatta). While certain properties of the solubilized and enriched enzyme remained relatively unchanged (molecular weight, kinetic profile, immunoprecipitatability), others exhibited marked shifts (specific activity, thermostability) as a function of aging. These changes contrasted with age-related alterations described in NADPH-cytochrome c (P-450) reductase isolated from inbred male rats. The present data suggest that inbred rodents may not accurately reflect possible age-dependent alterations in liver Phase I drug metabolism in primates.