title: Melatonin protects against apoptosis-inducing factor (AIF)-dependent cell death during acetaminophen-induced acute liver failure.
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.
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, China.
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Liang
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Liu
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.forename: Ye-Fa
authors.initials: YF
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport
chemical_list: D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D000082:Acetaminophen; D045304:Cytochromes c; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; D008550:Melatonin