title: Adenosine 5'-monophosphate blocks acetaminophen toxicity by increasing ubiquitination-mediated ASK1 degradation.
abstract: Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5'-monophsphate (5'-AMP). We demonstrated that co-administration of APAP and 5'-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function. The mechanism of protection by 5'-AMP was through inhibiting APAP-induced activation of JNK, and attenuating downstream c-jun and c-fos gene expression. This was triggered by attenuating apoptosis signal-regulated kinase 1(ASK1) methylation and increasing ubiquitination-mediated ASK1 protein degradation. Our findings indicate that replacing the current APAP with a safe and functional APAP/5'-AMP formulation could prevent APAP-induced hepatotoxicity.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
authors.forename: Yibei
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Xu
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
authors.forename: Jianfa
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000082:Acetaminophen; D000249:Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000494:pharmacology*; D059748:Proteolysis; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013997:Time Factors; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D020011:Protective Agents; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000082:Acetaminophen; D000249:Adenosine Monophosphate; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: 5′-AMP; APAP; ASK1; JNK; hepatotoxicity