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Author Xie, Yuchao ♦ Ramachandran, Anup ♦ Breckenridge, David G. ♦ Liles, John T. ♦ Lebofsky, Margitta ♦ Farhood, Anwar ♦ Jaeschke, Hartmut
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ APOPTOSIS ♦ GLUTATHIONE ♦ INHIBITION ♦ INJURIES ♦ LIVER ♦ METABOLIC ACTIVATION ♦ MICE ♦ MITOCHONDRIA ♦ MOLECULES ♦ NECROSIS ♦ OXIDATION ♦ OXIDIZERS ♦ PATIENTS ♦ SAFETY ♦ SIGNALS ♦ STRESSES ♦ TOXICITY
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 24 h 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 1.5 h 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. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1 inhibitor is not due to inhibition of APAP metabolism. • The ASK1 inhibitor prevents JNK activation and translocation to mitochondria. • Treatment with ASK1 inhibitors does not impair liver regeneration after APAP.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-07-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 286
Issue Number 1


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