Melatonin Protects against Apoptosis-Inducing Factor (AIF)-Dependent Cell Death during Acetaminophen-Induced Acute Liver Failure

作者：Liang, Ying-Li; Zhang, Zhi-Hui; Liu, Xiao-Jing; Liu, Xiao-Qian; Tao, Li; Zhang, Ye-Fa; Wang, Hua; Zhang, Cheng; Chen, Xi^*; Xu, De-Xiang

来源：PLos One, 2012, 7(12): e51911.

DOI：10.1371/journal.pone.0051911

• MITOCHONDRIAL OXIDANT STRESS
• FULMINANT HEPATIC-FAILURE
• ANTIOXIDANT ENZYMES
• DNA FRAGMENTATION
• BAX TRANSLOCATION
• OXIDATIVE STRESS
• INJURY
• MICE
• HEPATOTOXICITY
• PHOSPHORYLATION

Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure and is primarily caused by cytochrome P450 (CYP) 2E1-driven conversion of APAP into hepatotoxic metabolites. Several reports showed that melatonin attenuated APAP-induced acute liver failure. Nevertheless, the exact mechanism remains obscure. In the present study, we investigated the effects of melatonin on apoptosis-inducing factor (AIF)-dependent cell death in APAP-induced acute liver failure. Mice were intraperitoneally (i.p.) injected with different doses of melatonin (1.25, 5, 20 mg/kg) 30 min before APAP (300 mg/kg, i.p.). As expected, melatonin significantly alleviated APAP-induced cell death, as determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. Further analysis showed that melatonin significantly attenuated APAP-induced activation of the serine/threonine kinase receptor interacting protein 1 (RIP1). In addition, melatonin inhibited APAP-induced hepatic c-Jun N-terminal kinase (JNK) phosphorylation and mitochondrial Bax translocation. Correspondingly, melatonin inhibited APAP-induced translocation of AIF from mitochondria to nuclei. Interestingly, no changes were induced by melatonin on hepatic CYP2E1 expression. In addition, melatonin had little effect on APAP-induced hepatic glutathione (GSH) depletion. In conclusion, melatonin protects against AIF-dependent cell death during APAP-induced acute liver failure through its direct inhibition of hepatic RIP1 and subsequent JNK phosphorylation and mitochondrial Bax translocation.

• 出版日期2012-12-18
• 单位安徽医科大学