Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity.
Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity.
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DOI：
10.1517/17425255.2015.1071353
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发表时间：
2015
影响因子：
4.3
通讯作者：
Jaeschke H
中科院分区：
文献类型：
--
作者：
Du K;Xie Y;McGill MR;Jaeschke H
对乙酰氨基酚（APAP）过量是美国急性肝衰竭的主要原因。尽管在过去的几十年里，关于APAP肝毒性机制的研究取得了实质性进展，但治疗选择仍然有限，显然需要新的治疗方法。c-jun N-末端激酶（JNK）是近年来发现的一个很有前途的治疗靶点。早期研究确定JNK活化和线粒体易位在APAP肝毒性中的关键作用。然而，这一概念也受到了挑战。最初的研究未能再现JNK缺陷在APAP毒性中的保护作用，并且对JNK抑制剂甚至在敲除小鼠中的脱靶效应的担忧正在增加。有趣的是，最近的研究甚至表明，肝损伤可以改变或不影响JNK激活。目前的审查解决这些差异，并试图解释或调和一些相互矛盾的结果。JNK是APAP中毒的潜在治疗靶点。然而，关于其在APAP肝毒性中的实际作用仍存在争议。在JNK被认为是APAP中毒的相关治疗靶点之前，未来的研究需要在明确的临床前模型和人肝细胞中对特异性抑制剂进行更深入的测试。
Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. Although substantial progress regarding the mechanisms of APAP hepatotoxicity has been made in the past several decades, therapeutic options are still limited and novel treatments are clearly needed. c-jun N-terminal Kinase (JNK) has emerged as a promising therapeutic target in recent years. Early studies established the critical role of JNK activation and mitochondrial translocation in APAP hepatotoxicity. However, this concept has also been challenged. Initial studies failed to reproduce the protection of JNK deficiency in APAP toxicity and concerns over off-target effects of JNK inhibitors and even in knock-out mice are increasing. Interestingly, recent studies have even shown that liver injury can be altered with or without effects on JNK activation. The current review addresses these discrepancies and tries to explain or reconcile some of the conflicting results. JNK is a potential therapeutic target for APAP poisoning. However, controversies still exist regarding its actual role in APAP hepatotoxicity. Future studies are warranted for more in-depth testing of specific inhibitors in well-defined preclinical models and human hepatocytes before JNK can be considered a relevant therapeutic target for APAP poisoning.