Murray M, Cantrill E, Martini R, Farrell G C
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Arch Biochem Biophys. 1991 May 1;286(2):618-24. doi: 10.1016/0003-9861(91)90089-2.
In this study dietary vitamin A supplementation (25 IU/g diet) was assessed for its effect on hepatic microsomal P450 content and on P450 enzyme-specific drug oxidase activities in rats. Intake of the supplemented diet by male rats over a 15-week period resulted in a fivefold increase in hepatic vitamin A stores over those measured in control liver from rats that received a balanced diet without vitamin A supplementation. Serum retinol was unchanged and there was no evidence of hepatocellular injury in any of the animals. There was a 26% increase in P450 content in vitamin A-supplemented rat liver and regioselective androst-4-ene-3,17-dione (androstenedione) and progesterone hydroxylation revealed changes in several P450 pathways. Thus, androstenedione 16 alpha-hydroxylation (P450 IIC11-mediated) and progesterone 21-hydroxylation (P450 IIC6-mediated) were decreased slightly to 80 and 74% of respective control activities while P450 IIA1/2-dependent androstenedione 7 alpha-hydroxylation was slightly increased. In contrast, the 6 beta-hydroxylations of androstenedione and progesterone were increased to 169 and 152% of control following dietary supplementation. Kinetic analysis of androstenedione 6 beta-hydroxylation revealed an increase in maximal reaction velocity (Vmax 4.00 +/- 0.47 vs 2.20 +/- 0.10 nmol/min/mg protein) but the Km was unchanged, suggesting an increase in enzyme concentration. Consistent with this assertion, immunoquantitation of the steroid 6 beta-hydroxylase, P450 IIIA2, revealed a 158% increase in the microsomal expression of this enzyme (9.8 +/- 2.7 vs 6.2 +/- 1.3 ng/micrograms microsomal protein). From these studies it now seems clear that vitamin A, as a dietary additive in nontoxic doses, has the capacity to alter the activity of hepatic microsomal drug oxidases by modulating the expression of P450 enzymes.
在本研究中，评估了膳食补充维生素A（25 IU/g饮食）对大鼠肝微粒体P450含量及P450酶特异性药物氧化酶活性的影响。雄性大鼠在15周内摄入补充维生素A的饮食，其肝脏维生素A储备量比摄入不含维生素A补充剂的平衡饮食的对照大鼠肝脏中测得的储备量增加了五倍。血清视黄醇未发生变化，且所有动物均无肝细胞损伤的迹象。补充维生素A的大鼠肝脏中P450含量增加了26%，区域选择性雄甾-4-烯-3,17-二酮（雄烯二酮）和孕酮羟化反应显示几种P450途径发生了变化。因此，雄烯二酮16α-羟化反应（由P450 IIC11介导）和孕酮21-羟化反应（由P450 IIC6介导）分别略有下降，降至各自对照活性的80%和74%，而P450 IIA1/2依赖性雄烯二酮7α-羟化反应略有增加。相比之下，膳食补充后，雄烯二酮和孕酮的6β-羟化反应分别增加至对照的169%和152%。雄烯二酮6β-羟化反应的动力学分析显示最大反应速度增加（Vmax 4.00±0.47对2.20±0.10 nmol/min/mg蛋白），但米氏常数不变，表明酶浓度增加。与此论断一致，对类固醇6β-羟化酶P450 IIIA2进行免疫定量分析显示，该酶的微粒体表达增加了158%（9.8±2.7对6.2±1.3 ng/μg微粒体蛋白）。从这些研究中现在似乎可以明确，作为无毒剂量的膳食添加剂，维生素A有能力通过调节P450酶的表达来改变肝微粒体药物氧化酶的活性。
