Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity

被引:44
|
作者
Du, Kuo [1 ]
Xie, Yuchao [1 ]
McGill, Mitchell R. [1 ]
Jaeschke, Hartmut [1 ]
机构
[1] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA
关键词
acetaminophen; c-jun N-terminal kinase; drug hepatotoxicity; mitochondrial dysfunction; INDUCED LIVER-INJURY; APOPTOSIS-INDUCING FACTOR; TYROSINE-PHOSPHATASE; 1B; MITOCHONDRIAL PERMEABILITY TRANSITION; SIGNAL-REGULATING KINASE-1; OXIDANT STRESS; OXIDATIVE STRESS; CELL-DEATH; INSULIN-RECEPTOR; MICE;
D O I
10.1517/17425255.2015.1071353
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: 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.Areas covered: 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.Expert opinion: 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.
引用
收藏
页码:1769 / 1779
页数:11
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