The effects of aging on the hepatic microsomal mixed-function oxidase system of male and female monkeys.

Studies were conducted to determine the effects of aging on certain biochemical and biophysical properties of the hepatic microsomes and on the kinetic properties of a constituent drug-metabolizing enzyme and a heme protein in a nonhuman primate. Outbred male and female rhesus monkeys (Macaque mulatta) ranging in age from 1 to 25 years were employed as animal models. There was considerable individual variability, but no significant age or sex-related changes in (1) the concentration of microsomal protein or (2) the content of the cytochromes P-450. Although the oldest animals examined for NADPH cytochrome c (P-450) reductase activity were only 19 years of age, the specific activity of this important enzyme increased rather than decreased during aging. There were only minor changes in the total phospholipid content of the microsomes and none in the distribution profile of the major phospholipid classes. However, the microsomal cholesterol content increased sufficiently to cause a rise in the cholesterol/phospholipid ratio between 16 and 25 years of age. The fluidity of the membrane lipid domain exhibited a concomitant decline as measured by electron spin resonance spectroscopy. There was no apparent correlation between age-related changes in these physicochemical properties of the microsomes and the in vitro activities of the constituent drug-metabolizing enzymes or heme proteins. Furthermore, the marked disparities between the data obtained in inbred male rodents and those from outbred primates suggest that the extrapolation of the former to humans is of questionable value with respect to liver drug metabolism.