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Age-related changes in hepatic microsomal drug metabolism are substrate selective
Abstract:
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.
Insights
Aging alters liver drug metabolism in rats. Key components of the monooxygenase system, including cytochrome P-450, decrease with age, affecting how drugs are processed.
Area of Science:
- Biochemistry
- Pharmacology
- Gerontology
Background:
- Hepatic drug metabolism is crucial for xenobiotic detoxification.
- Aging is known to affect various physiological processes, including liver function.
- The cytochrome P-450 (CYP450) system plays a central role in drug metabolism.
Purpose of the Study:
- To investigate the age-related changes in hepatic microsomal monooxygenase components and drug metabolism activities in Fischer 344 rats.
- To determine how aging affects specific components of the drug-metabolizing enzyme system.
- To explore the relationship between changes in CYP450 and phospholipid components and altered drug metabolism.
Main Methods:
- Isolation of hepatic microsomes from male Fischer 344 rats at different age groups (young-adult, middle-aged, and old).
- Quantification of microsomal components: cytochrome P-450, cytochrome b5, NADPH-cytochrome c reductase, and phospholipids.
- Assay of drug metabolism activities using various substrates.
- Analysis of spectral properties (CO maximum) and polypeptide composition of microsomes.
Main Results:
- Microsomal cytochrome P-450, cytochrome b5, NADPH-cytochrome c reductase activity, and phospholipids decreased in middle-aged and old rats compared to young-adult rats.
- Enzymatic reduction of microsomal cytochrome P-450 remained unchanged with age.
- Drug metabolism activities showed variable changes (both decreases and increases) depending on the substrate used.
- Age-related differences were observed in spectral characteristics of reduced microsomal cytochrome P-450, microsomal fatty acid composition, and specific microsomal polypeptides (52,500 and 53,000 Da).
Conclusions:
- Aging significantly alters hepatic microsomal drug metabolism in rats.
- Qualitative changes in cytochrome P-450 and phospholipid components of the monooxygenase system likely contribute to the substrate-selective alterations in drug metabolism observed with aging.
- These findings highlight the impact of aging on liver drug detoxification pathways.