Wynne H, Mutch E, James O F, Rawlins M D, Woodhouse K W
Age Ageing. 1987 May;16(3):153-8. doi: 10.1093/ageing/16.3.153.
The clearance of many oxidized drugs falls with age. Whilst factors such as reduced liver size, blood flow and specific enzyme activity may be important, the possibility that reduced enzyme affinity for substrate contributes to this fall has not hitherto been investigated. Using liver microsomes from 12 young adult and 12 elderly male Norwegian Brown rats we defined the kinetics of ethoxyresorufin-O-de-ethylation and aldrin epoxidation, specific substrates for the 3-methylcholanthrene inducible and phenobarbitone inducible forms of cytochrome P450, respectively. Our results show a marked fall in the maximal activity of both enzymes in advanced age whether expressed in terms of microsomal protein or unit of cytochrome P450, but with no change in apparent enzyme affinity (Km). Since Km is unchanged, we feel that qualitative age-related changes in cytochrome P450 are unlikely. Reduced metabolism may be due to age-related alterations in coenzymes or smooth endoplasmic reticulum lipid membranes.
许多氧化药物的清除率会随着年龄的增长而下降。虽然肝脏大小、血流量和特定酶活性降低等因素可能很重要，但酶对底物的亲和力降低是否导致了这种下降，迄今为止尚未得到研究。我们使用了12只年轻成年挪威棕色雄性大鼠和12只老年挪威棕色雄性大鼠的肝微粒体，分别确定了乙氧试卤灵-O-脱乙基化和艾氏剂环氧化的动力学，这两种反应分别是细胞色素P450的3-甲基胆蒽诱导型和苯巴比妥诱导型的特异性底物。我们的结果表明，无论以微粒体蛋白还是细胞色素P450单位表示，两种酶的最大活性在高龄时均显著下降，但表观酶亲和力（Km）没有变化。由于Km不变，我们认为细胞色素P450不太可能存在与年龄相关的定性变化。代谢降低可能是由于辅酶或滑面内质网脂质膜的年龄相关改变所致。
