Abstract
Acetaminophen (APAP) is an analgesic–antipyretic drug and widely used in clinics. Its overdose may cause serious liver damage. Here, we examined the mechanistic role of c-Jun N-terminal kinase (JNK) signaling pathway in liver injury induced by different doses of APAP. Male mice were treated with APAP (150 and 175 mg·kg−1), and meanwhile JNK inhibitor SP600125 was used to interfere APAP-induced liver damage. The results showed that JNK signaling pathway was activated by APAP in a dose-dependent manner. C-Jun N-terminal kinase inhibitor decreased JNK and c-Jun activation significantly (P < 0.01) at 175 mg·kg−1 APAP dose, and phosphorylation levels of upstream proteins of JNK were also decreased markedly (P < 0.05). In addition, serum aminotransferases activities and hepatic oxidative stress increased in a dose-dependent manner with APAP treatment, but the levels of aminotransferases and oxidative stress decreased in mice treated with JNK inhibitor, which implied that JNK inhibition ameliorated APAP-induced liver damage. It was observed that apoptosis was increased in APAP-induced liver injury, and SP600125 can attenuate apoptosis through the inhibition of JNK phosphorylation. Meanwhile, glutathione S-transferases A1 (GSTA1) content in serum was enhanced, while GSTA1 content and expression in liver reduced significantly with administration of APAP (150 and 175 mg·kg−1). After inhibiting JNK, GSTA1 content in serum decreased significantly (P < 0.01); meanwhile, GSTA1 content and expression in liver enhanced. These findings suggested that JNK signaling pathway mediated APAP-induced hepatic injury, which was accompanied by varying GSTA1 content and expression in liver and serum.
Highlights
Drug-induced liver injury (DILI) is the leading cause of acute liver failure in western countries (Bernal et al, 2013)
The results showed that there was no significant difference in alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
The results showed that the expression of glutathione S-transferases A1 (GSTA1) decreased when mice were treated with APAP, but the expression level increased after inhibiting Jun N-terminal kinase (JNK) signaling pathway
Summary
Drug-induced liver injury (DILI) is the leading cause of acute liver failure in western countries (Bernal et al, 2013). Acetaminophen overdose causes acute liver failure due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis (Patterson et al, 2012). The hepatic injury model induced by APAP occupies an impregnable position in the study of liver disease. What’s more, it was reported that persistent exposure to hepatotoxic agents is clearly the primary inducer of hepatocellular carcinoma (Llovet et al, 2003). The molecular events of early hepatic injury caused by hepatotoxic agents are very important, which still need to be identified and could be a new target for precaution of hepatotoxic agents’ exposure
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