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.