Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice
Abstract
Treatment of mice with a toxic dose of acetaminophen (300 mg/kg, ip) significantly increased hepatotoxicity at 4 h, as evidenced by histological necrosis in the centrilobular areas of the liver, and increased serum levels of alanine aminotransferase (ALT) (from 8 +/- 1 IU/L in saline-treated mice to 3226 +/- 892 IU/L in the acetaminophen-treated mice). Serum levels of nitrate plus nitrite (a marker of nitric oxide synthesis) were also increased from 62 +/- 8 microM in saline-treated mice to 110 +/- 14 microM in acetaminophen-treated mice (P < 0.05). Regression analysis of serum ALT levels to serum nitrate plus nitrite levels in individual mice revealed a positive, linear relationship between serum ALT levels and serum nitrate plus nitrite levels with a correlation coefficient of 0.9 (P < 0.05). The y intercept value (nitrate plus nitrite level) was 63 +/- 15 microM. Immunohistochemical analysis of liver sections from acetaminophen-intoxicated mice using an anti-3-nitrotyrosine antibody indicated tyrosine nitration in the proteins of the centrilobular cells. Tyrosine nitration has been shown to occur by peroxynitrite, a reactive intermediate formed by an extremely rapid reaction of nitric oxide and superoxide and a species which also has hydroxyl radical-like activity. Analysis of liver sections using an anti-acetaminophen antiserum indicated the centrilobular cells also contained acetaminophen-protein adducts, a reaction of the metabolite N-acetyl-p-benzoquinone imine with cysteine residues on proteins. These data are consistent with acetaminophen metabolic activation leading to increased synthesis of nitric oxide and superoxide and to peroxynitrite as an important intermediate in the toxicity.
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Hepatic necrosis highly correlated with the areas of nitrated proteins.
“Hepatic necrosis highly correlated with the areas of nitrated proteins [91].”
Cites
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly
Beckman, J. S., & Koppenol, W. H. (1996) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1996.271.5.c1424 · Cited by 5,513 · see citing works
REDOX REGULATION OF CELLULAR ACTIVATION
Nakamura, H., Nakamura, K., & Yodoi, J. (1997) · Annual Review of Immunology · doi:10.1146/annurev.immunol.15.1.351 · Cited by 1,106 · see citing works
Nitric oxide and its role in the cardiovascular system
Loscalzo, J., & Welch, G. N. (1995) · Progress in Cardiovascular Diseases · doi:10.1016/s0033-0620(05)80001-5 · Cited by 599 · see citing works
Turning on the respiratory burst
Baggiolini, M., & Wymann, M. P. (1990) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(90)90179-f · Cited by 210 · see citing works
Mechanisms of Acetaminophen Toxicity: Immunochemical Detection of Drug-Protein Adducts
Hinson, J., Pumford, N. R., & Roberts, D. W. (1995) · Drug Metabolism Reviews · doi:10.3109/03602539509029816 · Cited by 102 · see citing works
Self-citationROLE OF MACROPHAGES IN ACETAMINOPHEN (PARACETAMOL)-INDUCED HEPATOTOXICITY
Goldin, R. D., Ratnayaka, I., BREACH, C. S., Brown, I. N., & Wickramasinghe, S. N. (1996) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199608)179:4 · Cited by 102 · see citing works
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Cover, C., Mansouri, A., Knight, T. R., Bajt, M. L., Lemasters, J. J., Pessayre, D., & Jaeschke, H. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.088898 · Cited by 373 · see citing works
James, L. P. (2003) · Toxicological Sciences · doi:10.1093/toxsci/kfg181 · Cited by 244 · see citing works
Oxidative stress responses of rats exposed to Roundup and its active ingredient glyphosate
El-Shenawy, N. S. (2009) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2009.06.001 · Cited by 207 · see citing works
Early Hepatic Microvascular Injury in Response to Acetaminophen Toxicity
ITO, Y., BETHEA, N. W., ABRIL, E. R., & MCCUSKEY, R. S. (2003) · Microcirculation · doi:10.1038/sj.mn.7800204 · Cited by 158 · see citing works
Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.10.004 · Cited by 123 · see citing works
“Hepatic necrosis highly correlated with the areas of nitrated proteins [91].”
BackgroundAgarwal, R., MacMillan-Crow, L. A., Rafferty, T. M., Saba, H., Roberts, D. W., Fifer, E. K., James, L. P., & Hinson, J. A. (2011) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.176321 · Cited by 116 · see citing works
Self-citationAbdelmegeed, M. A., Jang, S., Banerjee, A., Hardwick, J. P., & Song, B.-J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.02.018 · Cited by 85 · see citing works
Abdelmegeed, M. A., Moon, K.-H., Chen, C., Gonzalez, F. J., & Song, B.-J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.07.016 · Cited by 81 · see citing works
Deferoxamine delays the development of the hepatotoxicity of acetaminophen in mice
Schnellmann, J. G., Pumford, N. R., Kusewitt, D. F., Bucci, T. J., & Hinson, J. A. (1999) · Toxicology Letters · doi:10.1016/s0378-4274(99)00021-1 · Cited by 68 · see citing works
Self-citationUnderstanding peroxynitrite biochemistry and its potential for treating human diseases
Beckman, J. S. (2009) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2009.03.013 · Cited by 56 · see citing works
- Authors
- Hinson, J. A., Pike, S. L., Pumford, N. R., & Mayeux, P. R.
- Affiliations
- University of Arkansas Medical Center (US)
- University of Arkansas for Medical Sciences (US)
- Corresponding author
- Hinson, Jack A.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-05-23
- Volume
- 11
- Issue
- 6
- Pages
- 604-607
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- OpenAlex
- W2055420058
- Cited by
- 218
- References
- 6
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 8 · 2016: 9 · 2015: 13 · 2014: 16 · 2013: 12 · 2012: 8
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01gm048749-04)
- National Institute of General Medical Sciences (GM-48749)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK44716)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- acetaminophen hepatotoxicity, nitrotyrosine, protein adducts, peroxynitrite, nitric oxide, superoxide, N-acetyl-p-benzoquinone imine, centrilobular necrosis, alanine aminotransferase, metabolic activation, mice
- MeSH terms
- Acetaminophen, Alanine Transaminase, Animals, Biotransformation, Liver, Male, Nitrates, Nitric Oxide, Proteins, Tyrosine, Analgesics, Non-Narcotic, Mice
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