Mechanisms of acetaminophen-induced liver necrosis.
Mechanisms of acetaminophen-induced liver necrosis.
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DOI：
10.1007/978-3-642-00663-0_12
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发表时间：
2010
影响因子：
--
通讯作者：
James, Laura P
中科院分区：
文献类型：
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作者：
Hinson, Jack A;Roberts, Dean W;James, Laura P
虽然在治疗剂量下被认为是安全的，但在更高剂量下，对乙酰氨基酚会产生致命的小叶中心肝坏死。在今天的美国和英国，对乙酰氨基酚中毒约占所有急性肝衰竭病例的一半。该机制通过一系列复杂的事件发生。这些活动包括：（1）代谢为活性代谢物，其消耗谷胱甘肽并共价结合蛋白质;（2）在经历坏死变化的肝细胞中谷胱甘肽的损失伴随活性氧和氮物质的形成增加;（3）增加的氧化应激，与钙稳态的改变和信号转导应答的启动相关，引起线粒体渗透性转变;（4）伴随额外的氧化应激、线粒体膜电位的丧失和线粒体合成ATP的能力的丧失而发生的线粒体渗透性转变;和（5）导致坏死的ATP的丧失。与这些基本事件相关的似乎是一些炎症介质，如某些细胞因子和趋化因子，可以改变毒性。一些已被证明可以改变氧化应激，但这些调节剂与其他关键机制事件的关系尚未得到很好的描述。此外，现有数据支持细胞因子、趋化因子和生长因子参与再生过程的启动，导致肝脏结构和功能的重建。
Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.