Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury
Open accessAbstract
Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2h in mice exposed to a single APAP dose (350mg/kg ip), which caused severe liver necrosis at 24h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3-nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity.
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Protein nitration serves as one of the critical causal factors in APAP-induced acute liver damage usually observed at later time points.
“Thus, protein nitration serves as one of the critical causal factors in APAP-induced acute liver damage usually observed at later time points.”
NAC ameliorated the inactivation of the five critical enzymes via preventing Tyr nitration.
“Furthermore, NAC ameliorated the inactivation of the five critical enzymes via preventing Tyr nitration, as evidenced by immunoprecipitation with a specific antibody to each protein followed by immunoblot with anti-3-NT antibody.”
Treatment with NAC completely protected the liver from APAP-induced necrotic injury measured by increased serum transaminase activities and liver histology.
“Treatment with NAC completely protected the liver from the APAP-induced necrotic injury measured by increased serum transaminase activities and liver histology.”
More than 70 mitochondrial proteins and 30 cytosolic proteins were nitrated in APAP-exposed mice.
“In fact, after immunoaffinity purification followed by mass-spectral analysis, we demonstrated that more than 70 mitochondrial proteins and 30 cytosolic proteins were nitrated in APAP-exposed mice [94].”
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- Authors
- Abdelmegeed, M. A., Jang, S., Banerjee, A., Hardwick, J. P., & Song, B.-J.
- Affiliations
- National Institutes of Health (US)
- Northeast Ohio Medical University (US)
- Corresponding author
- Song, Byoung-Joon
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 60
- Pages
- 211-222
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC3680365
- OpenAlex
- W2009705589
- Cited by
- 85
- References
- 70
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 12 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 15 · 2014: 6 · 2013: 4
- FWCI
- 12.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- paracetamol, hepatotoxicity, protein nitration, nitrated proteins, mitochondrial dysfunction, N-acetylcysteine, antioxidant defense, nitrotyrosine, mitochondrial aldehyde dehydrogenase, Mn superoxide dismutase, glutathione peroxidase, ATP synthase, 3-ketoacyl-CoA thiolase, liver necrosis, oxidative stress
- MeSH terms
- Acetaminophen, Acetanilides, Acetylcysteine, Animals, Antioxidants, Mitochondria, Liver, Nitrates, Proteins, Superoxide Dismutase, Oxidative Stress, Mice, Chemical and Drug Induced Liver Injury
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