Abstract
Acetaminophen (APAP) is a commonly used analgesics and antipyretic agent. The therapeutic or recommended dose of APAP is not associated with adverse effects. However, intentional or unintentional overdose of APAP causes acute liver injury or acute liver failure if treatment is delayed. Currently, APAP-induced liver injury is one of the major causes of acute liver injury in the United States and other western countries. C-Jun N terminal kinase (JNK) implicated in stress-related signaling pathway plays an indispensable role in the mechanism of APAP hepatotoxicity. JNK mediates depletion of mitochondrial glutathione in the metabolic phase and enhances oxidative stress to aggravate liver injury. In addition, JNK plays an important role in APAP-induced apoptosis, necrosis or other forms of cell death. Furthermore, JNK plays a role in regulation of endogenous immune system and aseptic inflammatory responses induced by APAP. However, JNK may promote cell regeneration after APAP-induced cell death. The present review therefore highlights the functions of JNK in APAP-induced liver injury.
Key words : Acetaminophen; JNK; hepatotoxicity; signaling pathway;
Acetaminophen (APAP), also known as paracetamol or N-acetyl para-aminophenol, is a commonly used analgesic and antipyretic agent. The recommended dose of APAP is usually less than 4g/day and this dose is considered to be safe [1, 2]. However, excessive intake of APAP can cause acute liver injury which may progress to Acute Liver Failure (ALF). Notably, a previous study reported that a single dose of APAP > 125mg/kg can cause liver damage [3]. Currently, APAP-induced liver injury is a common cause of acute liver injury in the United States and most western countries.
C-Jun N terminal kinase (JNK) pathway is one of the 3 branches of the MAPK signaling pathway [4]. JNK is activated when cells are exposed to various forms of stress (osmotic stress, oxidative stress and radiation) or when they are treated with cytokines such as TNF and IL-1[4-6]. Therefore, JNK is considered to be a kinase activated by stress. JNK protein kinases are encoded by three genes, namely; JNK1, JNK2 and JNK3. JNK1 and JNK2 genes are expressed ubiquitously unlike JNK3 which has a more limited pattern of expression and is mainly expressed in the brain, heart and testis[4]. The aim of the present review was to explore the role of JNK in APAP-induced liver injury mainly focusing on JNK1 and JNK2 functions.
Acetyl-L-cysteine (NAC), the only FDA approved remedy for APAP-induced toxicity is a precursor for GSH that has a therapeutic effect against APAP overdose. NAC is only effective when administered during early phases of APAP toxicity, due to its narrow therapeutic window. JNK signaling pathway plays a significant role in APAP-induced liver injury. Therefore, JNK is a promising target for treatment of APAP hepatotoxicity. Therefore, this review summarizes the role of JNK in APAP-induced toxicity.