Abstract

The hepatic drug-metabolizing capacities of rodents and humans undergo marked age-dependent declines, particularly between maturity and senescence. This decline probably results from distinct qualitative and quantitative changes in the microsomal mixed function oxidase system. Previous studies reported age-related reductions in the amount of smooth surfaced endoplasmic reticulum membrane and the specific activities of several constituent enzymes of this drug-metabolizing system. The present study has subjected one of these enzymes, NADPH cytochrome c (P-450) reductase, to an extensive analysis and some of these data are reported here. The microsomal membranes of young Fischer 344 male rats (3 months) yielded approximately twice the enzyme recovered from those of old animals (27 months). Furthermore, the specific activity of the purified enzyme isolated from young animals was two-fold higher than that obtained from senescent rats. The “old” enzyme also exhibited an increased thermostability profile in comparison to the “young” enzyme. These data provide the first evidence of possible molecular alterations responsible for the well-documented age-dependent decline in the functional capacity of the rat liver microsomal mixed function oxidase system.

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