Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity
Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity
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DOI：
10.1006/niox.2001.0385
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发表时间：
2001-10-01
影响因子：
3.9
通讯作者：
Hinson, JA
中科院分区：
文献类型：
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作者：
Michael, SL;Mayeux, PR;Hinson, JA
我们最近报道，硝基酪氨酸和对乙酰氨基酚（APAP）-半胱氨酸蛋白加合物共定位于肝小叶中心细胞后，毒性剂量的A-PAP小鼠。而APAP加合物是通过代谢产物N-乙酰基-对苯醌亚胺与半胱氨酸反应形成的，硝基酪氨酸残基是通过酪氨酸与过氧亚硝酸盐反应形成的。过氧亚硝酸盐由一氧化氮（NO）和超氧化物形成。本文研究了APAP（300 mg/kg）在缺乏诱导型一氧化氮合酶活性的小鼠（NOS 2缺失或敲除小鼠; C57 BL/6-Nos 2（tm 1 Lau））和野生型小鼠中的肝毒性。在一段时间内，暴露的NOS 2敲除小鼠的ALT水平约为野生型小鼠的50%;然而，肝脏切片的组织学检查表明野生型和NOS 2敲除小鼠的小叶中心肝坏死水平相似。盐水处理的NOS 2缺失和野生型小鼠的血清硝酸盐和亚硝酸盐水平（NO合成）相同（53 +/- 2 μ M）。APAP仅增加野生型小鼠的NO合成。这种增加与ALT水平的增加一致，血清硝酸盐和亚硝酸盐的峰值水平在6小时（168 +/- 27 μ M）。在野生型小鼠中，相对于盐水处理的对照，肝脏酪氨酸硝化大大增加。NOS 2基因敲除小鼠的酪氨酸硝化也增加，但增加幅度较小，APAP仅增加NOS 2基因敲除小鼠的肝脏丙二醛水平（脂质过氧化）。结果表明，APAP介导的肝坏死存在多种途径，一种是通过硝基酪氨酸，如野生型小鼠，另一种是不依赖于诱导型一氧化氮合酶活性，但可能涉及增加超氧化物。(C)北京：科学出版社.
We recently reported that nitrotyrosine and acetaminophen (APAP)-cysteine protein adducts colocalize in the hepatic centrilobular cells following a toxic dose of A-PAP to mice. Whereas APAP-adducts are formed by reaction of the metabolite N-acetyl-p-benzoquinone imine with cysteine, nitrotyrosine residues are formed by reaction of tyrosine with peroxynitrite. Peroxynitrite is formed from nitric oxide (NO) and superoxide. This manuscript examines APAP (300 mg/kg) hepatotoxicity in mice lacking inducible nitric oxide synthase activity (NOS2 null or knockout mice; C57BL/6-Nos2(tm1Lau)) and in the wildtype mice. In a time course the ALT levels in the exposed NOS2 null mice were approximately 50% of the wildtype mice; however, histological examination of liver sections indicated similar levels of centrilobular hepatic necrosis in both wild-type and NOS2 null mice. Serum nitrate plus nitrite levels (NO synthesis) were identical in saline-treated NOS2 null and wild-type mice (53 +/- 2 muM). APAP increased NO synthesis in wild-type mice only. The increases paralleled the increases in ALT levels with peak levels of serum nitrate plus nitrite at 6 h (168 +/- 27 muM). In wild-type mice hepatic tyrosine nitration was greatly increased relative to saline treated controls. Tyrosine nitration increased in NOS2 null mice also, but the increase was much less. APAP increased hepatic malonaldehyde levels (lipid peroxidation) in NOS2 null mice only. The results suggest the presence of multiple pathways to APAP-mediated hepatic necrosis, one via nitrotyrosine, as in the wild-type mice, and another that is not dependent upon inducible nitric oxide synthase activity, but which may involve increased superoxide. (C) 2001 Academic Press.