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

Ying-Li Liang,Hua Wang,Cheng Zhang,Li Tao,Xiao-Jing Liu,De-Xiang Xu,Ye-Fa Zhang,Xiao-Qian Liu,Xi Chen,Zhi-Hui Zhang,Dominique Heymann

doi:10.1371/journal.pone.0051911

Ying-Li Liang, Hua Wang + Show 9 more

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https://doi.org/10.1371/journal.pone.0051911

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Journal: PloS one	Publication Date: Dec 18, 2012
Citations: 31	License type: CC BY 4.0

Affiliation: Anhui Medical University

Abstract

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.

Highlights

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug
We investigated the effects of melatonin on apoptosis-inducing factor (AIF)-dependent cell death in a mouse model of APAP-induced acute liver failure
We demonstrate for the first time that melatonin protects against AIF-dependent cell death during APAP-induced acute liver failure through its direct inhibition of hepatic receptor interacting protein 1 (RIP1) activation and subsequent Jun N-terminal kinase (JNK) phosphorylation and mitochondrial Bax translocation

Summary

Introduction

Safe at therapeutic doses, APAP overdose can cause severe acute liver damage characterized by centrilobular hepatic necrosis [1]. Increasing evidence demonstrates that apoptosis-inducing factor (AIF), which translocates to the nucleus and initiates nuclear DNA fragmentation, may be a critical mediator of APAP-induced cell death [3,4,5]. The prolonged activation of c-Jun N-terminal kinase (JNK) plays a key role in APAP-induced cell death [6]. An earlier report showed that leflunomide, antirheumatic drug, protected mice from APAP-induced acute liver damage through inhibition of JNK phosphorylation [7]. A recent study showed that arjunolic acid, a triterpenoid saponin, prevented from APAPinduced acute liver failure through inhibiting JNK-mediated activation of mitochondrial permeabilization [8]

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