title: Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury.
abstract: Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Breckenridge
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Liles
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Margitta
authors.initials: M
authors.lastname: Lebofsky
authors.affiliation: Department of Pathology, St. David's North Austin Medical Center, Austin, TX 78756, USA.
authors.forename: Anwar
authors.initials: A
authors.lastname: Farhood
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA. Electronic address: hjaeschke@kumc.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D008297:Male; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D005978:Glutathione; D019803:Glutathione Disulfide
keywords: ASK1; Acetaminophen; Hepatotoxicity; Oxidant stress; c-Jun N-terminal kinase
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