Effect of N-acetylcysteine on acetaminophen toxicity in mice: Relationship to reactive nitrogen and cytokine formation
Effect of N-acetylcysteine on acetaminophen toxicity in mice: Relationship to reactive nitrogen and cytokine formation
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DOI：
10.1093/toxsci/kfg181
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发表时间：
2003-10-01
影响因子：
3.8
通讯作者：
Hinson, JA
中科院分区：
文献类型：
--
作者：
James, LP;McCullough, SS;Hinson, JA
对乙酰氨基酚（APAP）反应性代谢产物的形成，硝基酪氨酸（NT）的生产，和细胞因子升高APAP毒性之间的关系进行了研究。小鼠给予300 mg/kg的APAP，并在1、2、4、8和12 h处死。血清天门冬氨酸氨基转移酶（AST）升高4 h。NT的相对含量与毒性相关，并定位于坏死细胞中。IL-1b在1 h升高，而IL-6、MIP-2和MCP-1在4-8 h升高。为了确定可逆性与毒性事件的重要性，N-乙酰半胱氨酸（NAC）之前APAP或1，2，或4小时后APAP给药小鼠。在12 h处死动物。APAP前NAC治疗导致血清AST、血清硝酸盐加亚硝酸盐（作为一氧化氮（NO）产生的量度）和肝细胞因子水平与对照组相似。在这些动物中不存在APAP蛋白加合物或NT。在NAC治疗1小时的小鼠中，细胞因子和血清AST在12小时是正常的，但APAP蛋白加合物存在于肝小叶中心区。这些动物中不存在NT。在2小时用NAC处理并在12小时处死的小鼠中，血清AST降低了80%。APAP加合物和NT存在于小叶中心区。在4小时接受NAC的小鼠对毒性和血清硝酸盐加亚硝酸盐没有保护作用。NT和细胞因子水平与单独接受APAP的小鼠相似。这些数据表明APAP毒性中的代谢事件与NO和IL-1b的上调之间存在关系。IL-6、MIP-2和MCP-1似乎遵循毒性。虽然这是一个先决条件，但共价结合本身似乎不是毒性发展中的毒性事件。
The relationship between acetaminophen (APAP) reactive metabolite formation, nitrotyrosine (NT) production, and cytokine elevation in APAP toxicity was investigated. Mice were dosed with 300 mg/kg of APAP and sacrificed at 1, 2, 4, 8, and 12 h. Serum aspartate aminotransferase (AST) was elevated by 4 h. The relative amount of NT correlated with toxicity and was localized in the necrotic cells. IL-1b was increased at 1 h, whereas IL-6, MIP-2, and MCP-1 were increased by 4-8 h. To determine the importance of reversible versus toxic events, N-acetylcysteine (NAC) was administered to mice either before APAP or 1, 2, or 4 h after APAP. The animals were sacrificed at 12 h. NAC treatment before APAP resulted in serum AST, serum nitrate plus nitrite as a measure of nitric oxide (NO) production, and hepatic cytokine levels that were similar to the controls. No APAP protein adducts or NT was present in these animals. In mice treated with NAC at 1 h, cytokines and serum AST were normal at 12 h, but APAP protein adducts were present in the hepatic centrilobular areas. No NT was present in these animals. In mice treated with NAC at 2 h and sacrificed at 12 h, serum AST was reduced by 80%. APAP adducts and NT were present in the centrilobular areas. Mice receiving NAC at 4 h had no protection from toxicity and serum nitrate plus nitrite. The NT and cytokine levels were similar to those of mice receiving APAP alone. The data suggest a relationship between metabolic events in APAP toxicity and the upregulation of NO, and IL-1b. IL-6, MIP-2, and MCP-1 appear to follow the toxicity. While it is a pre-requisite event, covalent binding per se does not appear to be a toxic event in the development of toxicity.