The transformation of glyceryl trinitrate and other nitrates by glutathione-organic nitrate reductase.
The transformation of glyceryl trinitrate and other nitrates by glutathione-organic nitrate reductase.
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谷胱甘肽有机硝酸还原酶对三硝酸甘油酯和其他硝酸盐的转化。
作者：
P. Needleman;F. E. Hunter
甘油三硝酸酯转化的主要途径似乎是在还原型谷胱甘肽（GSH）存在下的氢化。一分子三硝酸甘油酯与两个GSH反应，从2-或3-位释放一个无机亚硝酸根离子，形成1，3-或1，2-甘油二硝酸酯。用肝酶产生的甘油二硝酸酯和无机亚硝酸盐约占转化的甘油三硝酸酯的90%。三硝酸甘油酯降解反应没有产物抑制。甘油二硝酸酯的反硝化速率仅为甘油三硝酸酯的2-5%。单硝酸甘油酯几乎不受肝酶的影响。因此，甘油三硝酸酯的反硝化不会导致甘油形成。利用有机硝酸盐与GSH反应生成GSSG，建立了一种快速、灵敏的酶法测定方法。分光光度法或荧光法测量TPNH消失，因为GSSG被谷胱甘肽还原酶催化还原。甘露醇六硝酸酯、戊二醇四硝酸酯和甘油三硝酸酯在GSH存在下被肝可溶性酶快速转化，而硝酸异山梨酯和季戊四醇四硝酸酯被该系统以缓慢速率降解。这些化合物的反硝化导致许多具有较低数量的硝酸酯基团的产物。然而，母体分子不会发生完全降解。有机硝酸盐解毒的体内机制似乎与肝脏谷胱甘肽-有机硝酸盐还原酶观察到的酶促反应相似。
The major route for glyceryl trinitrate transformation appears to be denitration in the presence of reduced glutathione (GSH). One molecule of glyceryl trinitrate reacts with two GSH to release one inorganic nitrite ion from either the 2- or 3-position to form 1,3- or 1,2-glyceryl dinitrate. With liver enzyme the glyceryl dinitrates and inorganic nitrite produced account for about 90% of the glyceryl trinitrate transformed. There is no product inhibition of the glyceryl trinitrate degradation reaction. The denitration of glyceryl dinitrate proceeds at only 2-5% of the rate for glyceryl trinitrate. Glyceryl mononitrate is practically unaltered by the liver enzyme. Thus, the denitration of glyceryl trinitrate does not lead to glycerol formation. A rapid, sensitive enzymic assay based on the reaction of organic nitrates with GSH to yield GSSG was developed. The spectrophotometric or fluorometric method measures TPNH disappearance as the GSSG is catalytically reduced by glutathione reductase. Mannitol hexanitrate, erythrityl tetranitrate, and glyceryl trinitrate are rapidly transformed by the liver soluble enzyme in the presence of GSH, whereas isosorbide dinitrate and pentaerythritol tetranitrate are degraded at a slow rate by this system. The denitration of these compounds leads to a number of products with a lower number of nitrate ester groups. However, complete degradation of the parent molecule does not occur. The in vivo mechanism of organic nitrate detoxication appears to be similar to the enzymic denitration observed with liver glutathione-organic nitrate reductase.