Ramachandran Anup, Lebofsky Margitta, Yan Hui-Min, Weinman Steven A, Jaeschke Hartmut
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA.
Arch Toxicol. 2015 May;89(5):773-83. doi: 10.1007/s00204-015-1498-5. Epub 2015 Mar 6.
Chronic hepatitis C virus (HCV) infection predisposes patients to develop liver failure after acetaminophen (APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected. HCV transgenic mice with higher liver injury had lower liver glutathione levels, elevated mitochondrial oxidative stress and enhanced release of apoptosis-inducing factor (AIF) from the mitochondria. This was accompanied by induction of a higher ER stress response and induction of autophagy. Transgenic animals showing protection against liver injury had a robust recovery of liver glutathione content at 6 h when compared to wild-type animals, accompanied by reduction in mitochondrial oxidative stress and AIF release. This was accompanied by an elevation in glutathione S-transferase mRNA levels and activity, which suggests that an efficient clearance of the reactive intermediate may contribute to the protection against APAP hepatotoxicity in these mice. These results demonstrate that while HCV infection could exacerbate APAP-induced liver injury due to induction and amplification of mitochondrial oxidant stress, it could also protect against injury by activation of APAP scavenging mechanisms.
慢性丙型肝炎病毒（HCV）感染使患者在对乙酰氨基酚（APAP）过量服用后易发生肝衰竭。利用表达HCV结构蛋白核心、E1和E2的转基因小鼠探索其中涉及的机制。用200mg/kg体重的APAP处理C57BL/6J小鼠，6小时时出现显著肝损伤，表现为谷丙转氨酶（ALT）水平升高、局灶性小叶中央坏死和核DNA片段化。HCV转基因小鼠表现出不同的反应，约一半动物的所有肝损伤参数均加重，而另一半则受到保护。肝损伤较重的HCV转基因小鼠肝谷胱甘肽水平较低，线粒体氧化应激升高，线粒体凋亡诱导因子（AIF）释放增加。这伴随着更高的内质网应激反应诱导和自噬诱导。与野生型动物相比，对肝损伤具有保护作用的转基因动物在6小时时肝谷胱甘肽含量强劲恢复，同时线粒体氧化应激和AIF释放减少。这伴随着谷胱甘肽S-转移酶mRNA水平和活性升高，这表明活性中间体的有效清除可能有助于保护这些小鼠免受APAP肝毒性。这些结果表明，虽然HCV感染可因线粒体氧化应激的诱导和放大而加重APAP诱导的肝损伤，但也可通过激活APAP清除机制来预防损伤。
