The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation
The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation
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DOI：
10.1172/jci59755
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发表时间：
2012-04-01
影响因子：
15.9
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
McGill, Mitchell R.;Sharpe, Matthew R.;Jaeschke, Hartmut
对乙酰氨基酚（APAP）过量是美国急性肝衰竭的主要原因。毒性始于与蛋白质结合的活性代谢物。在啮齿动物中，这导致线粒体功能障碍和核DNA片段化，导致坏死性细胞死亡。虽然APAP代谢在人类中相似，但尚未在患者中研究导致毒性的后期事件。在这项研究中，测量了APAP过量患者血浆中线粒体损伤生物标志物（谷氨酸脱氢酶[GDH]和线粒体DNA [mtDNA]）和核DNA片段的水平。肝功能检查（LT）正常的无肝损伤或肝损伤轻微的过量给药患者（本文称为正常LT组）和健康志愿者作为对照组。异常LT患者血浆中GDH活性峰值和mtDNA浓度增加。异常LT队列中的核DNA片段化峰值也比对照组增加。在小鼠中的平行研究显示，这些血浆生物标志物与组织损伤相关性良好。Caspase-3活性和裂解的Caspase-3在过量患者或小鼠的血浆中检测不到，但在TNF诱导的细胞凋亡后升高，表明APAP过量不会引起细胞凋亡。因此，我们的研究结果表明，线粒体的损伤和核DNA断裂可能是APAP肝毒性的关键事件，导致坏死细胞死亡。
Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondria' dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondria' damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.