Influence of aging and induction on rat liver and kidney microsomal mixed function oxidase systems

Abstract

In an effort to investigate the diminished capacity of old individuals to metabolize certain drugs we studied the effect of old age on the concentrations and inductibility of the hepatic and renal mixed function oxidase systems of rats. One group of rats (4, 12, and 36 months old) were induced with phenobarbital (PB) and another group (7 and 31 months old) with β-naphthoflavone (BNF). Cytochrome P-450, cytochrome b 5, and NADPH-cytochrome P-450 reductase concentrations were determined in control and PB-induced liver or BNF-induced liver and kidney microsomes. In vivo rates of R-warfarin metabolism catalyzed by liver and kidney microsomes were used as a probe of the forms of cytochrome P-450 present. Livers and kidneys were judged to be free of significant histologic lesions. Hepatic and renal cytochrome P-450 and cytochrome b 5 concentrations were increased by BNF induction while PB induction increased hepatic cytochrome P-450 and did not affect cytochrome b 5. Hepatic NADPH-cytochrome P-450 reductase activities were increased by PB induction and decreased by BNF induction while activity of the renal enzyme was increased by BNF induction. Cytochrome P-450 concentrations were lower in old control and induced livers and kidneys. Aging also decreased concentrations of renal cytochrome b 5 and NADPH-cytochrome P-450 reductase. The inducibility of hepatic cytochrome P-450 by PB was also diminished in old rats. From the results of aging on R-warfarin metabolite patterns it was determined that the activity of the major form of cytochrome P-450, BNF-B in BNF-induced rats was unaltered in the livers and significantly diminished in the kidneys of old rats. Two forms of cytochrome P-450 in PB-induced rats, PB-C and PB-B, demonstrated diminished ability to be induced and PB-C showed diminished activity in old rats.