McDonald B J, Bennett B M
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Can J Physiol Pharmacol. 1990 Dec;68(12):1552-7. doi: 10.1139/y90-236.
The vascular biotransformation of organic nitrates appears to be a prerequisite for their action as vasodilators. In the current study, we assessed the involvement of cytochrome P-450 in the denitration of glyceryl trinitrate and the enantiomers of isoidide dinitrate. Denitration of organic nitrates by the microsomal fraction of rat liver was NADPH dependent and followed apparent first-order kinetics. Under aerobic conditions, the t1/2 of D-isoidide dinitrate was significantly shorter than that of L-isoidide dinitrate (11.9 vs. 14.1 min, p less than or equal to 0.05), which is consistent with the greater potency of the D-enantiomer for vasodilation. Under anaerobic conditions, the denitration of glyceryl trinitrate was very rapid (t1/2 approximately 30 s). Organic nitrate biotransformation was inhibited by carbon monoxide, SKF 525A, and dioxygen. This suggests that the biotransformation of organic nitrates can occur through the direct interaction with the heme moiety of cytochrome P-450. The biotransformation of glyceryl trinitrate was catalyzed preferentially by those isoenzymes induced by phenobarbital. The biotransformation of glyceryl trinitrate was regioselective for 1,3-glyceryl dinitrate formation except in phenobarbital-induced microsomes under aerobic conditions, in which preferential formation of 1,2-glyceryl dinitrate occurred. These data suggest that cytochrome P-450 is involved in the biotransformation of organic nitrates and raises the possibility that vascular cytochrome P-450 may play a role in the mechanism-based biotransformation of organic nitrates, the result of which is vascular smooth muscle relaxation.
有机硝酸盐的血管生物转化似乎是其作为血管扩张剂发挥作用的前提条件。在本研究中，我们评估了细胞色素P-450在硝酸甘油和异山梨醇二硝酸酯对映体脱硝过程中的作用。大鼠肝脏微粒体部分对有机硝酸盐的脱硝作用依赖于NADPH，并遵循明显的一级动力学。在有氧条件下，D-异山梨醇二硝酸酯的t1/2明显短于L-异山梨醇二硝酸酯（11.9对14.1分钟，p≤0.05），这与D-对映体更强的血管扩张效力一致。在无氧条件下，硝酸甘油的脱硝非常迅速（t1/2约30秒）。一氧化碳、SKF 525A和双氧抑制有机硝酸盐的生物转化。这表明有机硝酸盐的生物转化可通过与细胞色素P-450的血红素部分直接相互作用而发生。硝酸甘油的生物转化优先由苯巴比妥诱导的那些同工酶催化。除了在有氧条件下苯巴比妥诱导的微粒体中优先形成1,2-甘油二硝酸酯外，硝酸甘油的生物转化对1,3-甘油二硝酸酯的形成具有区域选择性。这些数据表明细胞色素P-450参与有机硝酸盐的生物转化，并增加了血管细胞色素P-450可能在基于机制的有机硝酸盐生物转化中发挥作用的可能性，其结果是血管平滑肌松弛。
