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Title: c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity

Abstract

Acetaminophen (APAP) overdose, which causes liver injury in animals and humans, activates c-jun N-terminal kinase (JNK). Although it was shown that the JNK inhibitor SP600125 effectively reduced APAP hepatotoxicity, the mechanisms of protection remain unclear. C57Bl/6 mice were treated with 10 mg/kg SP600125 or vehicle (8% dimethylsulfoxide) 1 h before 600 mg/kg APAP administration. APAP time-dependently induced JNK activation (detected by JNK phosphorylation). SP600125, but not the vehicle, reduced JNK activation, attenuated mitochondrial Bax translocation and prevented the mitochondrial release of apoptosis-inducing factor at 4-12 h. Nuclear DNA fragmentation, nitrotyrosine staining, tissue GSSG levels and liver injury (plasma ALT release and necrosis) were partially attenuated by the vehicle (- 65%) and completely eliminated by SP600125 (- 98%) at 6 and 12 h. Furthermore, SP600125 attenuated the increase of inducible nitric oxide synthase (iNOS) mRNA and protein. However, APAP did not enhance plasma nitrite + nitrate levels (NO formation); SP600125 had no effect on this parameter. The iNOS inhibitor L-NIL did not reduce NO formation or injury after APAP but prevented NO formation caused by endotoxin. Since SP600125 completely eliminated the increase in hepatic GSSG levels, an indicator of mitochondrial oxidant stress, it is concluded that the inhibition of peroxynitrite wasmore » mainly caused by reduced superoxide formation. Our data suggest that the JNK inhibitor SP600125 protects against APAP-induced liver injury in part by attenuation of mitochondrial Bax translocation but mainly by preventing mitochondrial oxidant stress and peroxynitrite formation and thereby preventing the mitochondrial permeability transition pore opening, a key event in APAP-induced cell necrosis.« less

Authors:
 [1];  [2];  [1]
  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)
  2. Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425 (United States)
Publication Date:
OSTI Identifier:
21460183
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 246; Journal Issue: 1-2; Other Information: DOI: 10.1016/j.taap.2010.04.015; PII: S0041-008X(10)00142-0; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; GLUTATHIONE; INJURIES; LIVER; MICE; MITOCHONDRIA; NITRIC OXIDE; NITRITES; OXIDIZERS; PHOSPHOTRANSFERASES; STRESSES; ANIMALS; BODY; CELL CONSTITUENTS; CHALCOGENIDES; DIGESTIVE SYSTEM; DISEASES; DRUGS; ENZYMES; GLANDS; MAMMALS; NITROGEN COMPOUNDS; NITROGEN OXIDES; ORGANIC COMPOUNDS; ORGANS; OXIDES; OXYGEN COMPOUNDS; PEPTIDES; PHOSPHORUS-GROUP TRANSFERASES; POLYPEPTIDES; PROTEINS; RADIOPROTECTIVE SUBSTANCES; RESPONSE MODIFYING FACTORS; RODENTS; TRANSFERASES; VERTEBRATES

Citation Formats

Saito, Chieko, Lemasters, John J, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, and Jaeschke, Hartmut. c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.04.015.
Saito, Chieko, Lemasters, John J, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, & Jaeschke, Hartmut. c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. United States. https://doi.org/10.1016/j.taap.2010.04.015
Saito, Chieko, Lemasters, John J, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, and Jaeschke, Hartmut. 2010. "c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity". United States. https://doi.org/10.1016/j.taap.2010.04.015.
@article{osti_21460183,
title = {c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity},
author = {Saito, Chieko and Lemasters, John J and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425 and Jaeschke, Hartmut},
abstractNote = {Acetaminophen (APAP) overdose, which causes liver injury in animals and humans, activates c-jun N-terminal kinase (JNK). Although it was shown that the JNK inhibitor SP600125 effectively reduced APAP hepatotoxicity, the mechanisms of protection remain unclear. C57Bl/6 mice were treated with 10 mg/kg SP600125 or vehicle (8% dimethylsulfoxide) 1 h before 600 mg/kg APAP administration. APAP time-dependently induced JNK activation (detected by JNK phosphorylation). SP600125, but not the vehicle, reduced JNK activation, attenuated mitochondrial Bax translocation and prevented the mitochondrial release of apoptosis-inducing factor at 4-12 h. Nuclear DNA fragmentation, nitrotyrosine staining, tissue GSSG levels and liver injury (plasma ALT release and necrosis) were partially attenuated by the vehicle (- 65%) and completely eliminated by SP600125 (- 98%) at 6 and 12 h. Furthermore, SP600125 attenuated the increase of inducible nitric oxide synthase (iNOS) mRNA and protein. However, APAP did not enhance plasma nitrite + nitrate levels (NO formation); SP600125 had no effect on this parameter. The iNOS inhibitor L-NIL did not reduce NO formation or injury after APAP but prevented NO formation caused by endotoxin. Since SP600125 completely eliminated the increase in hepatic GSSG levels, an indicator of mitochondrial oxidant stress, it is concluded that the inhibition of peroxynitrite was mainly caused by reduced superoxide formation. Our data suggest that the JNK inhibitor SP600125 protects against APAP-induced liver injury in part by attenuation of mitochondrial Bax translocation but mainly by preventing mitochondrial oxidant stress and peroxynitrite formation and thereby preventing the mitochondrial permeability transition pore opening, a key event in APAP-induced cell necrosis.},
doi = {10.1016/j.taap.2010.04.015},
url = {https://www.osti.gov/biblio/21460183}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1-2,
volume = 246,
place = {United States},
year = {Thu Jul 15 00:00:00 EDT 2010},
month = {Thu Jul 15 00:00:00 EDT 2010}
}