Toxicological Sciences 62, 212-220 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Vascular and Hepatocellular Peroxynitrite Formation during Acetaminophen Toxicity: Role of Mitochondrial Oxidant Stress
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
Peroxynitrite may be involved in acetaminophen-induced liver damage. However, it is unclear if peroxynitrite is generated in hepatocytes or in the vasculature. To address this question, we treated C3Heb/FeJ mice with 300 mg/kg acetaminophen and assessed nitrotyrosine protein adducts as indicator for peroxynitrite formation. Vascular nitrotyrosine staining was evident before liver injury between 0.5 and 2 h after acetaminophen treatment. However, liver injury developed parallel to hepatocellular nitrotyrosine staining between 2 and 6 h after acetaminophen. The mitochondrial content of glutathione disulfide, as indicator of reactive oxygen formation determined 6 h after acetaminophen, increased from 2.8 ± 0.6% in controls to 23.5 ± 5.1%. A high dose of allopurinol (100 mg/kg) strongly attenuated acetaminophen protein-adduct formation and prevented the mitochondrial oxidant stress and liver injury after acetaminophen. Lower doses of allopurinol, which are equally effective in inhibiting xanthine oxidase, were not protective and had no effect on nitrotyrosine staining and acetaminophen protein adduct formation. In vitro experiments showed that allopurinol is not a direct scavenger of peroxynitrite. We conclude that there is vascular peroxynitrite formation during the first 2 h after acetaminophen treatment. On the other hand, reactive metabolites of acetaminophen bind to intracellular proteins and cause mitochondrial dysfunction and superoxide formation. Mitochondrial superoxide reacts with nitric oxide to form peroxynitrite, which is responsible for intracellular protein nitration. The pathophysiological relevance of vascular peroxynitrite for hepatocellular peroxynitrite formation and liver injury remains to be established.
Key Words: peroxynitrite; nitrotyrosine; acetaminophen; allopurinol; liver failure; mitochondria; oxidant stress.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. Savransky, C. Reinke, J. Jun, S. Bevans-Fonti, A. Nanayakkara, J. Li, A. C. Myers, M. S. Torbenson, and V. Y. Polotsky Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice Exp Physiol, February 1, 2009; 94(2): 228 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Bajt, H.-M. Yan, A. Farhood, and H. Jaeschke Plasminogen Activator Inhibitor-1 Limits Liver Injury and Facilitates Regeneration after Acetaminophen Overdose Toxicol. Sci., August 1, 2008; 104(2): 419 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Rao, Y. S. Ziegler, I. X. McLeod, J. R. Yates, and A. M. Nardulli Effects of Cu/Zn Superoxide Dismutase on Estrogen Responsiveness and Oxidative Stress in Human Breast Cancer Cells Mol. Endocrinol., May 1, 2008; 22(5): 1113 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Bajt, A. Farhood, J. J. Lemasters, and H. Jaeschke Mitochondrial Bax Translocation Accelerates DNA Fragmentation and Cell Necrosis in a Murine Model of Acetaminophen Hepatotoxicity J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 8 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Botta, S. Shi, C. C. White, M. J. Dabrowski, C. L. Keener, S. L. Srinouanprachanh, F. M. Farin, C. B. Ware, W. C. Ladiges, R. H. Pierce, et al. Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice J. Biol. Chem., September 29, 2006; 281(39): 28865 - 28875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Yohe, K. A. O'Hara, J. A. Hunt, T. J. Kitzmiller, S. G. Wood, J. L. Bement, W. J. Bement, J. G. Szakacs, S. A. Wrighton, J. M. Jacobs, et al. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1269 - G1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, A. Nivorozhkin, and C. Szabo Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., March 1, 2006; 58(1): 87 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke and M. L. Bajt Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death Toxicol. Sci., January 1, 2006; 89(1): 31 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cover, A. Mansouri, T. R. Knight, M. L. Bajt, J. J. Lemasters, D. Pessayre, and H. Jaeschke Peroxynitrite-Induced Mitochondrial and Endonuclease-Mediated Nuclear DNA Damage in Acetaminophen Hepatotoxicity J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 879 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. G. Lei and W.-H. Cheng New Roles for an Old Selenoenzyme: Evidence from Glutathione Peroxidase-1 Null and Overexpressing Mice J. Nutr., October 1, 2005; 135(10): 2295 - 2298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke Comments on "Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells" J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1401 - 1402. [Full Text] [PDF]
|
|
|
|
|
|
C. Cover, P. Fickert, T. R. Knight, A. Fuchsbichler, A. Farhood, M. Trauner, and H. Jaeschke Pathophysiological Role of Poly(ADP-Ribose) Polymerase (PARP) Activation during Acetaminophen-Induced Liver Cell Necrosis in Mice Toxicol. Sci., March 1, 2005; 84(1): 201 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Bajt, T. R. Knight, J. J. Lemasters, and H. Jaeschke Acetaminophen-Induced Oxidant Stress and Cell Injury in Cultured Mouse Hepatocytes: Protection by N-Acetyl Cysteine Toxicol. Sci., August 1, 2004; 80(2): 343 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ito, E. R. Abril, N. W. Bethea, and R. S. McCuskey Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G60 - G67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Knight, M. W. Fariss, A. Farhood, and H. Jaeschke Role of Lipid Peroxidation as a Mechanism of Liver Injury after Acetaminophen Overdose in Mice Toxicol. Sci., November 1, 2003; 76(1): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Bajt, T. R. Knight, A. Farhood, and H. Jaeschke Scavenging Peroxynitrite with Glutathione Promotes Regeneration and Enhances Survival during Acetaminophen-Induced Liver Injury in Mice J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 67 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Knight, Y.-S. Ho, A. Farhood, and H. Jaeschke Peroxynitrite Is a Critical Mediator of Acetaminophen Hepatotoxicity in Murine Livers: Protection by Glutathione J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 468 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kohen and A. Nyska Invited Review: Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for Their Quantification Toxicol Pathol, October 1, 2002; 30(6): 620 - 650. [Abstract] [PDF]
|
|
|
|
|
|
J. S. Gujral, T. R. Knight, A. Farhood, M. L. Bajt, and H. Jaeschke Mode of Cell Death after Acetaminophen Overdose in Mice: Apoptosis or Oncotic Necrosis? Toxicol. Sci., June 1, 2002; 67(2): 322 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke, G. J. Gores, A. I. Cederbaum, J. A. Hinson, D. Pessayre, and J. J. Lemasters Mechanisms of Hepatotoxicity Toxicol. Sci., February 1, 2002; 65(2): 166 - 176. [Abstract] [Full Text] [PDF]
|
|