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.

Aging↗

PubMedDate not supplied

Aging effects on hepatic NADPH cytochrome P450 reductase, CYP2B1&2, and polymeric immunoglobulin receptor mRNAs in male Fischer 344 rats.

Aging perturbs the expression of many liver proteins, but the mechanisms remain unresolved. Expression of hepatic NADPH cytochrome P450 reductase, phenobarbital-induced CYP2B1&2, and the polymeric immunoglobulin receptor (pIgR) decline as a function of aging. We examined the effect of aging on the expression of the mRNA transcripts of these proteins, as well as those of alpha 2u-globulin and beta-actin in male F344 rats. Despite age-related losses in the expression of P450 reductase and plasma membrane-bound pIgR in the rat liver (approximately 30-50%), aging is is accompanied by 1) no change and 2) a modest decline (< 20%) in their respective mRNA steady state levels. On the other hand, the expression of phenobarbital-induced microsomal CYP2B1&2 and the steady state level of its mRNA exhibit parallel age-dependent shifts. The mRNA transcript for alpha 2u-globulin declines between maturity and old age, whereas the beta-actin mRNA level remains unchanged. These preliminary data are consistent with previous studies which suggest that aging may perturb hepatic CYP2B1&2 and alpha 2u-globulin at the transcriptional level, whereas changes in the expression of P450 reductase and pIgR may reflect posttranscriptional modifications.

Actins↗

PubMedDate not supplied

Effects of aging on the properties of rhesus monkey liver microsomal NADPH-cytochrome c (P-450) reductase.

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.

Aging↗