Schmucker D L, Vessey D A, Wang R K, James J L, Maloney A
Mech Ageing Dev. 1984 Oct 15;27(2):207-17. doi: 10.1016/0047-6374(84)90046-0.
Aging results in a significant decline in liver drug metabolism which is largely attributable to changes in the microsomal mixed function oxidase system. For example, the mixed function oxidase system in the livers of senescent rats is characterized by: (1) a reduced cytochrome P-450 content; (2) a decline in the specific activity of NADPH-cytochrome c (P-450) reductase; and (3) a slower rate of ethylmorphine N-demethylation in comparison to young adult animals. Since several factors intrinsic to the microsomes may influence the efficacy of the mixed function oxidase system, e.g. the phospholipid and cholesterol contents, the saturation index of the fatty acids and the fluidity of the membranes, we conducted a physicochemical analysis of liver microsomes isolated from young adult (3-4 months), mature (12-16 months) and senescent (25-27 months) male Fischer rats. Although the microsomal cholesterol content did not change appreciably between maturity and senescence, there was a marked decline in the total phospholipid content. This resulted in a significant increase in the cholesterol/phospholipid ratio, 0.49 to 0.65 between 16 and 27 months of age. The age-related changes in the total phospholipid content were largely reflected in each of the major fractions, i.e. phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine + phosphatidylserine. Small increases in the relative percentages of highly unsaturated fatty acid species were offset by similar decreases in the more frequent and more saturated species as a function of increased age. As a result, the net change in the fatty acid saturation index was probably minimal. However, the increase in the cholesterol/phospholipid ratio most likely contributes to the significant decline in the order parameter of microsomes isolated from old rats which, in turn, may impair the functional capacity of the hepatic mixed function oxidase system.
衰老导致肝脏药物代谢显著下降，这在很大程度上归因于微粒体混合功能氧化酶系统的变化。例如，衰老大鼠肝脏中的混合功能氧化酶系统具有以下特征：（1）细胞色素P-450含量降低；（2）NADPH-细胞色素c（P-450）还原酶的比活性下降；（3）与年轻成年动物相比，乙基吗啡N-脱甲基化速率较慢。由于微粒体的几个内在因素可能影响混合功能氧化酶系统的功效，例如磷脂和胆固醇含量、脂肪酸的饱和度指数以及膜的流动性，我们对从年轻成年（3 - 4个月）、成熟（12 - 16个月）和衰老（25 - 27个月）雄性Fischer大鼠分离的肝脏微粒体进行了物理化学分析。尽管微粒体胆固醇含量在成熟和衰老之间没有明显变化，但总磷脂含量显著下降。这导致胆固醇/磷脂比值显著增加，在16至27个月龄之间从0.49增加到0.65。总磷脂含量的年龄相关变化在每个主要组分中都有很大反映，即磷脂酰胆碱、磷脂酰肌醇和磷脂酰乙醇胺 + 磷脂酰丝氨酸。随着年龄的增加，高度不饱和脂肪酸种类相对百分比的小幅增加被更常见和更饱和种类的类似减少所抵消。因此，脂肪酸饱和度指数的净变化可能很小。然而，胆固醇/磷脂比值的增加很可能导致从老年大鼠分离的微粒体有序参数显著下降，这反过来可能损害肝脏混合功能氧化酶系统的功能能力。
