title: Mitogen-activated protein kinase phosphatase (Mkp)-1 protects mice against acetaminophen-induced hepatic injury.
abstract: c-Jun N-terminal kinase (JNK) activation promotes hepatocyte death during acetaminophen overdose, a common cause of drug-induced liver failure. While mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a critical negative regulator of JNK MAPK, little is known about the role of Mkp-1 during hepatotoxicity. In this study, we evaluated the role of Mkp-1 during acute acetaminophen toxicity. Mkp-1⁺/⁺ and Mkp-1⁻/⁻ mice were dosed ip with vehicle or acetaminophen at 300 mg/kg (for mechanistic studies) or 400 mg/kg (for survival studies). Tissues were collected 1-6 hr post 300 mg/kg dosing to assess glutathione levels, organ damage, and MAPK activation. Mkp-1⁻/⁻ mice exhibited more rapid plasma clearance of acetaminophen than did Mkp-1⁺/⁺ mice, indicated by a quicker decline of plasma acetaminophen level. Moreover, Mkp-1⁻/⁻ mice suffered more severe liver injury, indicated by higher plasma alanine transaminase activity and more extensive centrilobular apoptosis and necrosis. Hepatic JNK activity in Mkp-1⁻/⁻ mice was higher than in Mkp-1⁺/⁺ mice. Finally, Mkp-1⁻/⁻ mice displayed a lower overall survival rate and shorter median survival time after dosing with 400 mg/kg acetaminophen. The more severe phenotype exhibited by Mkp-1⁻/⁻ mice indicates that Mkp-1 plays a protective role during acute acetaminophen overdose, potentially through regulation of JNK.
authors.affiliation: Department of Veterinary Bioscience, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA.
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Wancket
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Meng
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D005978:Glutathione