Melatonin Protects Against Acetaminophen-induced Hepatocyte Death

Objective Acetaminophen (APAP) overdose is the most frequent cause of acute liverfailure and is primarily caused by cytochrome P450(CYP)2E1-driven conversion ofAPAP into hepatotoxic metabolites. Several reports showed that melatonin attenuatedAPAP-induced acute liver failure. Nevertheless, the exact mechanism remains obscure.In the present study, we investigated the effects of melatonin on apoptosis-inducingfactor (AIF)-dependent cell death in APAP-induced acute liver failure.Methods Mice were intraperitoneally (i.p.) injected with different doses of melatonin(1.25,5,20mg/kg)30min before APAP (300mg/kg, i.p.). By Western blot,immunohistochemistry, quantitative real-time PCR and biochemical methods to detectthe molecular and cellular indicators.Results As expected, melatonin significantly alleviated APAP-induced cell death, asdetermined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. Furtheranalysis showed that melatonin significantly attenuated APAP-induced activation of theserine/threonine kinase receptor interacting protein1(RIP1). In addition, melatonininhibited APAP-induced hepatic c-Jun N-terminal kinase (JNK) phosphorylation andmitochondrial Bax translocation. Correspondingly, melatonin inhibited APAP-inducedtranslocation of AIF from mitochondria to nuclei. Interestingly, no changes wereinduced by melatonin on hepatic CYP2E1expression. In addition, melatonin had littleeffect on APAP-induced hepatic glutathione (GSH) depletion.Conclusion Melatonin protects against AIF-dependent cell death duringAPAP-induced acute liver failure through its direct inhibition of hepatic RIP1and subsequent JNK phosphorylation and mitochondrial Bax translocation.