NITRIC OXIDE AND THE METABOLISM OF TOXIC CHEMICALS AND DRUGS

人们普遍认为，CCl4的肝脏毒性 CCl4代谢为游离三氯甲基的结果 自由基由细胞色素P-450产生。这种自由基和相关的反应 物种通过启动脂质过氧化和 与蛋白质共价结合，最终导致细胞死亡。 早期的研究报告说，亚致死剂量的CCl4处理的兔子 对致死效应的敏感性是正常兔子的120倍 细菌内毒素。从肠道吸收的内毒素会变成 通过与腹膜和腹膜的相互作用而参与肝脏毒性 脾巨噬细胞和枯否细胞。这些细胞，当 受刺激，产生活性介质，包括氧衍生的 自由基、肿瘤坏死因子、白三烯和 一氧化氮(NO)，从而造成细胞损伤。因此，它是 一氧化氮在肝坏死过程中可能起重要作用 由毒物引起。体内NO的产生及其在体内的作用 暴露于肝脏毒物的实验动物还没有 在此之前演示了这项工作。NO在体内被检测为亚铁 血红蛋白亚硝基复合体、P450-NO、HbNO等和AS 来源不明的铁-硫二亚硝基络合物。不是 络合作用抑制P450，NO刺激鸟苷环化酶， 但总的来说，不应该导致不可逆转的损害。在……里面 相比之下，蛋白质的硝基酪氨酸含量已成为一种 常用的不可逆检测技术 一氧化氮依赖的氧化组织损伤。硝基酪氨酸的形成 通常被解释为体内过氧亚硝酸盐形成的证据。 我们发现了一种依赖酪氨酸的自由基， 生成硝基酪氨酸的不依赖过氧亚硝酸盐的路线。

It is widely accepted that the hepatotoxicity of CCl4 results from the metabolism of CCl4 to the trichloromethyl free radical by cytochrome P-450. This free radical and related reactive species cause cellular damage by initiating lipid peroxidation and covalently binding to protein, ultimately leading to cell death. Earlier studies reported that sublethally CCl4-treated rabbits were 120 times more susceptible than normal rabbits to the lethal effect of bacterial endotoxin. Endotoxin absorbed from the gut becomes involved in hepatotoxicity by its interaction with peritoneal and splenic macrophages and Kupffer cells. These cells, when stimulated, produce reactive mediators, including oxygen-derived free radicals, tumor necrosis factor- (TNF- ), leukotrienes, and nitric oxide ( NO), thereby causing cellular damage. Therefore it is plausible that NO plays an important role during hepatic necrosis caused by toxicants. In vivo NO production and its role in experimental animals exposed to hepatotoxicants had not been demonstrated before this work. NO is detected in vivo as ferrous hemoproteins nitrosyl complexes, P450-NO, HbNO, etc. and as iron-sulfur dinitrosyl complexes of unknown origin. NO complexation inhibits P450 and NO stimulates guanylate cyclase, but in general is not thoought to lead to irreversible damage. In contrast, protein nitrotyrosine formation content has become a frequently used technique for the detection of irreversible NO-dependent oxidative tissue damage. Formation of nitrotyrosine is usually interpreted as proof of in vivo peroxynitrite formation. We have discovered a tyrosyl radical-dependent, peroxynitrite-independent route to nitrotyrosine formation.