Acetaminophen-induced hepatotoxicity
Acetaminophen-induced hepatotoxicity
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DOI：
10.1124/dmd.31.12.1499
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发表时间：
2003-12-01
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：
James, LP;Mayeux, PR;Hinson, JA
过量服用止痛剂醋氨酚会导致潜在的致命性肝小叶中心坏死。1970年代，吉列博士的实验室描述了毒性的初始阶段。这些发现表明，对乙酰氨基酚被细胞色素P450酶代谢活化，成为一种活性代谢产物，耗尽谷胱甘肽（GSH）并与蛋白质共价结合。结果表明，GSH的补充可防止其毒性。这一发现导致了目前使用的解毒剂N-乙酰半胱氨酸的发展。随后确定反应性代谢产物为N-乙酰基-对苯醌亚胺（NAPQI）。尽管已证明共价结合与毒性有很好的相关性，但已证明还会发生许多其他事件，并且可能在毒性的引发和修复中很重要。最近的数据表明，硝化酪氨酸残基以及对乙酰氨基酚加合物发生在中毒剂量的对乙酰氨基酚后的坏死细胞中。硝基酪氨酸被认为是由过氧亚硝酸盐介导的，过氧亚硝酸盐是一种由超氧化物和一氧化氮（NO）快速反应形成的活性氮物质。过氧亚硝酸盐通常被GSH解毒，GSH在对乙酰氨基酚毒性中被耗尽。NO合成（血清硝酸盐加亚硝酸盐）显着增加后，对乙酰氨基酚。在诱导型一氧化氮合酶（iNOS）基因敲除小鼠，对乙酰氨基酚没有增加NO合成或酪氨酸硝化，但是，组织学证据表明没有差异的毒性。对乙酰氨基酚在野生型小鼠中不引起肝脏脂质过氧化，但在iNOS敲除小鼠中引起脂质过氧化。这些数据表明，NO可能发挥作用，在控制脂质过氧化反应和活性氮/氧物种可能是重要的毒性。超氧化物的来源尚未确定，但我们最近的发现，NADPH氧化酶敲除小鼠对对乙酰氨基酚同样敏感，酪氨酸的硝化作用相同，这表明超氧化物不是来自库普弗细胞的激活。据推测，NAPQI介导的线粒体损伤可能是超氧化物的来源。此外，细胞因子和趋化因子在毒性和修复过程的发展中的重要性已被最近的几项研究所证实。IL-1 β在对乙酰氨基酚中毒早期升高，可能在诱导iNOS中起重要作用。其他细胞因子，如IL-10，巨噬细胞抑制蛋白-2（MIP-2）和单核细胞趋化蛋白-1（MCP-1），似乎参与肝细胞修复和促炎细胞因子的调节。
The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1beta is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 ( MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.