NITRIC OXIDE AND THE METABOLISM OF TOXIC CHEMICALS AND DRUGS

工作总结：人们普遍认为，四氯化碳的肝毒性 结果从四氯化碳代谢为三氯甲基自由基 细胞色素P-450 这种自由基和相关的活性物质 通过引发脂质过氧化和共价结合引起细胞损伤 与蛋白质结合最终导致细胞死亡早期研究 报道称，亚致死剂量的四氯化碳处理过的兔子， 比正常的兔子更容易受到细菌的致死作用， 内毒素 从肠道吸收的内毒素参与了 通过与腹膜和脾巨噬细胞相互作用产生肝毒性 和枯否细胞。 这些细胞在受到刺激时， 介质，包括氧源性自由基，肿瘤坏死因子， α（TNF-α）、白三烯和一氧化氮（NO），从而引起 细胞损伤因此，似乎NO在这一过程中起着重要的作用。 在毒物引起的肝坏死中的作用。体内NO生成 在暴露于肝毒物的实验动物中， 在这项工作之前已经证明。体内检测到NO为亚铁 血红素蛋白亚硝酰基复合物、P450-NO、HbNO等，以及作为铁-硫 来源不明的二亚硝基复合物。NO络合抑制P450， 一氧化氮刺激鸟苷酸环化酶，但一般来说， 造成不可逆的伤害相反，蛋白质硝基酪氨酸的形成 内容已经成为用于检测 不可逆的NO依赖性氧化组织损伤。形成 硝基酪氨酸通常被解释为体内过氧亚硝酸盐的证据 阵 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。

Summary of Work: 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- alpha (TNF-alpha), 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.