Age-dependent alterations in rat liver microsomal NADPH-cytochrome c (P-450) reductase: a qualitative and quantitative analysis.

The hepatic drug-metabolizing capacities of rodents and man exhibit age-dependent declines. The extensive use of medication in geriatric patients demonstrates the need to characterize the mechanism(s) responsible for this reduced liver function. An analysis of microsomal NADPH-cytochrome c (P-450) reductase in young adult (3 months), mature (9 months) and senescent (27 months) male Fischer 344 rats revealed specific age-related qualitative and quantitative changes in this enzyme. The specific activity of the purified enzyme from young animals was two-fold higher than that recovered from the other age groups. In addition, there was: (1) no change in molecular weight, (2) alterations in heat inactivation profiles, (3) an apparent reduction in substrate affinity, and (4) a two-fold loss of enzyme activity per unit of immunoprecipitable material as a function of animal age. Our data suggest that this important liver drug-metabolizing enzyme undergoes post-translational modifications in its conformation which are reflected in the above parameters and which, ultimately, affect its efficacy.