NITRIC OXIDE AND THE METABOLISM OF TOXIC CHEMICALS AND DRUGS

一氧化氮与有毒化学品和药物的代谢

• 批准号: 6106716
• 负责人: RONALD P MASON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6106716
• 关键词: Kupffer's cell; bacterial toxins; carbon tetrachloride; cytochrome P450; cytotoxicity; dexamethasone; drug metabolism; electron spin resonance spectroscopy; endotoxins; enzyme inhibitors; free radicals; hemoglobin; hemoprotein; hepatotoxin; isozymes; laboratory rabbit; laboratory rat; leukotrienes; macrophage; monocyte; nitric oxide; nitric oxide synthase; protective chemical group; toxin metabolism; tumor necrosis factor alpha

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.

人们普遍认为，四氯化碳的肝毒性 结果从四氯化碳代谢到三氯甲基游离 细胞色素P-450。这种自由基和相关的反应性 物种通过引发脂质过氧化而引起细胞损伤， 与蛋白质共价结合，最终导致细胞死亡。 早期的研究报道，亚致死四氯化碳处理的兔子， 对致死效应的敏感性比正常兔子高120倍 细菌内毒素从肠道吸收的内毒素 通过其与腹膜的相互作用参与肝毒性， 脾巨噬细胞和枯否细胞。这些细胞，当 刺激，产生反应介质，包括氧衍生的 自由基、肿瘤坏死因子（TNF-）、白三烯和 一氧化氮（NO），从而导致细胞损伤。因此 可能NO在肝坏死过程中起重要作用 由有毒物质引起的。体内NO的产生及其在 暴露于肝毒性物质的实验动物没有被 在这项工作之前，NO在体内以亚铁形式被检测到 血红素蛋白亚硝酰基复合物、P450-NO、HbNO等， 来源不明的铁硫二亚硝酰络合物。没有 复合抑制P450和NO刺激鸟苷酸环化酶， 但一般不认为会导致不可逆转的损害。在 相比之下，蛋白质硝基酪氨酸形成含量已成为一个 常用于检测不可逆 NO依赖性氧化性组织损伤。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酰自由基的 过氧亚硝酸盐独立的路线硝基酪氨酸形成。