The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity
The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity
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DOI：
10.1016/s0378-4274(03)00239-x
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发表时间：
2003-10-15
影响因子：
3.5
通讯作者：
Bajt, ML
中科院分区：
文献类型：
--
作者：
Jaeschke, H;Knight, TR;Bajt, ML
对乙酰氨基酚（AAP）过量可导致实验动物和人类严重的肝毒性，甚至肝衰竭。尽管在过去的30年里进行了大量的努力，但AAP诱导的肝细胞损伤的机制仍然没有完全理解。广泛接受的是，损伤过程是由AAP代谢成反应性代谢物引发的，其首先耗尽谷胱甘肽，然后结合到细胞蛋白，包括许多线粒体蛋白。该过程的一个结果可能是观察到的线粒体呼吸、ATP耗竭和线粒体氧化应激的抑制。在存在足够的维生素E的情况下，活性氧的形成不会引起严重的脂质过氧化，但超氧化物与一氧化氮反应形成过氧亚硝酸盐，这是一种强大的氧化剂和硝化剂。过氧亚硝酸盐可修饰细胞大分子，并可能加重线粒体功能障碍和ATP耗竭，导致肝细胞和窦内皮细胞的细胞坏死。因此，我们推测，活性代谢物的形成和蛋白质结合启动损伤过程，这可能是线粒体功能障碍和过氧亚硝酸盐的形成，然后传播和放大。这一概念也调和了过去许多有争议的发现，并为AAP过量后肝细胞损伤的机制提供了一个可行的假设。(C)2003爱思唯尔爱尔兰有限公司保留所有权利。
Acetaminophen (AAP) overdose can cause severe hepatotoxicity and even liver failure in experimental animals and humans. Despite substantial efforts over the last 30 years, the mechanism of AAP-induced liver cell injury is still not completely understood. It is widely accepted that the injury process is initiated by the metabolism of AAP to a reactive metabolite, which first depletes glutathione and then binds to cellular proteins including a number of mitochondrial proteins. One consequence of this process may be the observed inhibition of mitochondrial respiration, ATP depletion and mitochondrial oxidant stress. In the presence of sufficient vitamin E, reactive oxygen formation does not induce severe lipid peroxidation but the superoxide reacts with nitric oxide to form peroxynitrite, a powerful oxidant and nitrating agent. Peroxynitrite can modify cellular macromolecules and may aggravate mitochondrial dysfunction and ATP depletion leading to cellular oncotic necrosis in hepatocytes and sinusoidal endothelial cells. Thus, we hypothesize that reactive metabolite formation and protein binding initiate the injury process, which may be then propagated and amplified by mitochondrial dysfunction and peroxynitrite formation. This concept also reconciles many of the controversial findings of the past and provides a viable hypothesis for the mechanism of hepatocellular injury after AAP overdose. (C) 2003 Elsevier Ireland Ltd. All rights reserved.