Pathophysiological significance of c-junN-terminal kinase in acetaminophen hepatotoxicity

Abstract

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.

Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity

“…In addition, MT did not affect JNK activation and the translocation of activated (phosphorylated) JNK to the mitochondria. Since the initial mitochondrial dysfunction is thought to be responsible for activation of MAP kinases, which ultimately result in JNK activation (reviewed in Du et al 2015b), the fact that MT did not prevent JNK activation suggests that MT did not affect these early signaling events. In contrast, MT eliminated NT staining and attenuated GSSG formation.…”

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

“…Apparently, intracellular ROS increments activate the Mitogen-Activated Protein Kinases (MAPK) cascade resulting in sustained JNK phosphorylation (71–74), which sensitizes the mitochondria to JNK signaling. A consequence of p-JNK translocation into the mitochondria is that it provides a second hint that amplifies oxidative stress and promotes MPT formation (75). More specifically, P-JNK binds to Src homology 3 domain binding protein 5 (Sh3bp5 or Sab) on the outer mitochondrial membrane, which then promotes mitochondrial ROS production by a mechanism not yet fully understood.…”

Noncoding RNAs as therapeutics for acetaminophen-induced liver injury

“…However, when sulfation is saturated (8), additional quantities of APAP are metabolized by Cyp2E1 and NAPQI accumulation initiates liver toxicity. Excess NAPQI causes significant depletion of glutathione, protein adduct formation especially in mitochondria (9,10) and a mitochondrial oxidative and nitrosative stress (11), which is then amplified by translocation of c-Jun N-terminal kinase (JNK) to the mitochondria (12,13). This triggers the opening of the mitochondrial permeability transition pore resulting in collapse of the membrane potential, cessation of ATP formation, and matrix swelling (14).…”