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The effects of methyltestosterone administration (100 mg/kg for four days) on the hepatic microsomal drug-metabolizing system from old male rats was investigated. Age-related decreases in cytochrome P-450 content, cytochrome c reductase activity and benzphetamine N-demethylase activity were unaffected by methyltestosterone treatment. Administration of the androgen induced nitroanisole O-demethylase and aniline hydroxylase activities, resulting in a restoration of the latter to levels found in young-adult animals.

Hepatic microsomal monooxygenase induction was investigated in young-adult and middle-aged male Fischer 344 rats. Monooxygenase components and drug metabolism activities were determined in liver microsomes prepared from rats treated with phenobarbital (PB, beta-naphthoflavone (BNF) or methyltestosterone (MT) and compared with values from untreated rats. PB and BNF effects on cytochrome P-450 concentration and cytochrome c reductase activity were similar in young-adult and middle-aged animals. However, the extent of cytochrome P-450 induction by MT was less in the older animals. The age-related changes in induction of drug metabolism activities differed with different substrates for the monooxygenase system. In contrast to the inducibility of benzphetamine N-demethylation and aniline hydroxylation, which was diminished in the older rats, the inducibility of nitroanisole O-demethylation was enhanced. The results imply that qualitative changes in the microsomal enzyme system occurred as the animals progress from young to middle adulthood.

The influence of aging on hepatic microsomal monooxygenase induction by phenobarbital (PB) or beta-naphthoflavone (BNF) was investigated in male Fischer 344 rats maintained in a constant environment. PB-induced increases in microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity were similar in rats aged 3-5 months (young-adult) and 24-25 months (old), but increased in benzephetamine N-demethylase activity were markedly diminished in the old rats. Separation of hepatic microsomal proteins by sodium dodecylsulfate gel electrophoresis demonstrated that aging decreased the induction by PB of a polypeptide with a molecular weight of 52,500. BNF-induced increases in microsomal cytochrome P-450 and nitroanisole O-demethylase activity were greater in old than in young-adult rats, and BNF induction of 55,000 and 57,000 molecular weight microsomal polypeptides was increased slightly in livers from old rats. The results indicate that age-related effects on monooxygenase induction vary with different inducers of the hepatic microsomal enzyme system.

Microsomes were isolated from livers of male Fischer 344 rats at 3 to 5, 14 to 15 and 24 to 25 months of age for the determination of monooxygenase components and drug metabolism activities. Microsomal cytochrome P-450, cytochrome b5, NADPH-cytochrome c reductase activity and phospholipid were decreased in middle-aged and old rats compared with young-adult rats, but the enzymatic reduction of microsomal cytochrome P-450 was unchanged. Drug metabolism activities both decreased and increased as a consequence of aging, depending upon the substrate used. Differences were observed between young-adult and old rats in the CO maximum of reduced microsomal cytochrome P-450, in microsomal fatty acid composition and in the amounts of microsomal polypeptides having molecular weights of 52,500 and 53,000. The substrate selectivity of the age-related alterations in hepatic microsomal drug metabolism may be due to qualitative changes in the cytochrome P-450 and phospholipid components of the monooxygenase system.