Forum - Mechanisms of hepatotoxicity
Forum - Mechanisms of hepatotoxicity
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DOI：
10.1093/toxsci/65.2.166
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发表时间：
2002-02-01
影响因子：
3.8
通讯作者：
Lemasters, JJ
中科院分区：
文献类型：
--
作者：
Jaeschke, H;Gores, GJ;Lemasters, JJ
本综述阐述了肝毒性特定机制的最新进展。由于肝脏具有独特的代谢以及与胃肠道的关系，它是药物、外源性物质和氧化应激毒性的重要靶点。在胆汁淤积性疾病中，内源性生成的胆汁酸通过刺激Fas从细胞质转位到质膜（在质膜上发生自身聚集从而触发细胞凋亡）而导致肝细胞凋亡。枯否细胞激活和中性粒细胞浸润会扩大毒性损伤。枯否细胞释放活性氧物质（ROS）、细胞因子和趋化因子，这些物质诱导中性粒细胞渗出和激活。肝脏表达多种细胞色素P450同工酶，包括乙醇诱导的CYP2E1。CYP2E1产生ROS，激活许多在毒理学上重要的底物，并且可能是乙醇引起氧化应激的核心途径。在对乙酰氨基酚中毒时，一氧化氮（NO）清除超氧阴离子产生过氧亚硝酸盐，过氧亚硝酸盐进而导致蛋白质硝化和组织损伤。在诱导型一氧化氮合酶（iNOS）基因敲除小鼠中，硝化作用被阻止，但未被清除的超氧阴离子产生会导致有毒的脂质过氧化反应发生。微泡性脂肪变性、非酒精性脂肪性肝炎（NASH）和溶细胞性肝炎涉及线粒体功能障碍，包括线粒体脂肪酸β - 氧化受损、线粒体呼吸抑制以及线粒体DNA损伤。线粒体通透性转换（MPT）的诱导是导致线粒体功能衰竭的另一种机制，如果ATP没有完全耗尽，它可导致因ATP耗尽而坏死或半胱天冬酶依赖性细胞凋亡。由于这些机制多种多样，肝毒性仍然是药物从药物研发和临床使用中撤回的一个主要原因。
This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid beta-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.