Zannoni V G, Sato P H
Fed Proc. 1976 Nov;35(13):2464-9.
There is increasing evidence that the liver microsomal drug metabolizing system is affected by various vitamins such as ascorbic acid, riboflavin, and alpha-tocopherol. In regard to ascorbic acid deficiency there is a decrease in the quantity of hepatic microsomal electron transport components such as cytochrome P-450 and NADPH-cytochrome P-450 reductase, as well as decreases in a variety of drug enzyme reactions such as N-demethylation, O-demethylation, and steroid hydroxylation. In addition, young animals given high supplements of vitamin C have increased quantities of electron transport components and overall drug metabolism activities. Kinetic studies indicate no change in the apparent Km of N-demethylase, O-demethylase or hydroxylase for drug substrates in animals depleted or given high amounts of the vitamin. However, there are qualitative changes in both type I and II substrate-cytochrome P-450 binding. Ascorbic acid is not involved in microsomal lipid peroxidation or in any qualitative or quantitative change in phosphatidylcholine. Replenishing vitamin C-deficient animals with ascorbic acid required 3 to 7 days for the electron transport components and drug metabolism activities to return to normal levels. Induction with phenobarbital and 3-methylcholanthrene is not impaired in the deficient animal since drug metabolism activities are induced to the same extent as normal controls; however, the administration of delta-aminolevulinic acid, a precursor of heme synthesis, to deficient animals caused an increase in the quantity of cytochrome P-450. The effects of riboflavin deficiency on electron transport components and drug metabolism activities have been noted only in adult animals after prolonged periods of deficiency. Decreases in drug metabolism activities occur with both type I (aminopyrine and ethylmorphine) and type II (aniline) substrates. As was found with ascorbic acid deficiency, drug enzyme induction occurred to the same extent with phenobarbital in deficient and normal animals. In addition, it required from 10 to 15 days for the drug metabolism activities to return to normal levels when deficient animals were replenished with riboflavin. The effect of vitamin E on drug metabolism is specific in N-demethylase activities decrease while O-demethylase activities are not affected in the deficient state. This vitamin differs from ascorbic acid and riboflavin in that several laboratories have reported no quantitative decrease in cytochrome P-450, although there are some reports that it and delta-aminolevulinic acid dehydratase are lowered quantity of cytochrome in E-deficient animals. The effect of vitamin E, if any, on the P-450 is unresolved; an important question that requires further clarification. As with ascorbic acid there is no difference in the apparent Km of N-demethylase enzymes for varous substrates and the protective effect of vitamin E does not appear to be one of an antioxidant inhibiting microsomal lipid peroxidation.
越来越多的证据表明，肝脏微粒体药物代谢系统会受到多种维生素的影响，如抗坏血酸、核黄素和α-生育酚。关于抗坏血酸缺乏，肝脏微粒体电子传递成分的数量会减少，如细胞色素P-450和NADPH-细胞色素P-450还原酶，同时多种药物酶反应也会减少，如N-去甲基化、O-去甲基化和类固醇羟化反应。此外，给予高剂量维生素C的幼龄动物，其电子传递成分的数量和整体药物代谢活性会增加。动力学研究表明，在缺乏或给予高剂量该维生素的动物中，N-去甲基酶、O-去甲基酶或羟化酶对药物底物的表观Km没有变化。然而，I型和II型底物与细胞色素P-450的结合存在质的变化。抗坏血酸不参与微粒体脂质过氧化，也不引起磷脂酰胆碱的任何质或量的变化。用抗坏血酸补充维生素C缺乏的动物，电子传递成分和药物代谢活性需要3至7天才能恢复到正常水平。在缺乏抗坏血酸的动物中，苯巴比妥和3-甲基胆蒽的诱导作用不受影响，因为药物代谢活性被诱导到与正常对照相同的程度；然而，给缺乏抗坏血酸的动物施用血红素合成前体δ-氨基乙酰丙酸，会导致细胞色素P-450的数量增加。核黄素缺乏对电子传递成分和药物代谢活性的影响仅在成年动物长期缺乏后才被注意到。I型（氨基比林和乙基吗啡）和II型（苯胺）底物的药物代谢活性都会降低。与抗坏血酸缺乏时一样，在缺乏核黄素和正常的动物中，苯巴比妥诱导药物酶的程度相同。此外，当给缺乏核黄素的动物补充核黄素时，药物代谢活性需要10至15天才能恢复到正常水平。维生素E对药物代谢的影响具有特异性，在缺乏维生素E的状态下，N-去甲基酶活性降低，而O-去甲基酶活性不受影响。这种维生素与抗坏血酸和核黄素不同，因为几个实验室报告细胞色素P-450没有定量减少，尽管有一些报告称在缺乏维生素E的动物中它和δ-氨基乙酰丙酸脱水酶降低了细胞色素的量。维生素E对P-450的影响（如果有的话）尚未解决；这是一个需要进一步澄清的重要问题。与抗坏血酸一样，N-去甲基酶对各种底物的表观Km没有差异，维生素E的保护作用似乎不是通过抑制微粒体脂质过氧化的抗氧化作用。
