Novel Mechanisms of Protection Against Acetaminophen Hepatotoxicity in Mice by Glutathione and N-Acetylcysteine
Open accessAbstract
Acetaminophen (APAP) overdose is a major cause of acute liver failure. The glutathione (GSH) precursor N -acetylcysteine (NAC) is used to treat patients with APAP overdose for up to 48 hours. Although it is well established that early treatment with NAC can improve the scavenging of the reactive metabolite N -acetyl - p -benzoquinone imine, protective mechanisms at later times remain unclear. To address this issue, fasted C3Heb/FeJ mice were treated with 300 mg/kg APAP and then received intravenously 0.65 mmol/kg GSH or NAC at 1.5 hours after APAP. The animals were sacrificed at 6 hours. APAP alone caused severe liver injury with peroxynitrite formation and DNA fragmentation, all of which was attenuated by both treatments. However, GSH (−82%) was more effective than NAC (−46%) in preventing liver injury. Using nuclear magnetic resonance spectroscopy to measure tissue adenosine triphosphate (ATP) levels and the substrate flux through the mitochondrial Krebs cycle, it was observed that the reduced liver injury correlated with accelerated recovery of mitochondrial GSH content, maintenance of ATP levels, and an increased substrate supply for the mitochondrial Krebs cycle compared with APAP alone. NAC treatment was less effective in recovering ATP and mitochondrial GSH levels and showed reduced substrate flux through the Krebs cycle compared with GSH. However, increasing the dose of NAC improved the protective effect similar to GSH, suggesting that the amino acids not used for GSH synthesis were used as mitochondrial energy substrates. Conclusion: Delayed treatment with GSH and NAC protect against APAP overdose by dual mechanisms—that is, by enhancing hepatic and mitochondrial GSH levels (scavenging of reactive oxygen and peroxynitrite)—and by supporting the mitochondrial energy metabolism. (Hepatology 2009.)
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Acetylcysteine is an effective antidote for paracetamol overdose.
“Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur.”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [98]
NAC allows for the detoxification of NAPQI and prevents hepatotoxicity in most cases.
“This allows for the detoxification of NAPQI and prevents hepatotoxicity in most cases [98].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [98]
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- Authors
- Saito, C., Zwingmann, C., & Jaeschke, H.
- Affiliations
- University of Kansas Medical Center (US)
- Hôpital Saint-Luc (CA)
- Corresponding author
- Jaeschke, Hartmut
- ORCID
- Jaeschke, Hartmut
- Venue
- Hepatology
- Published
- 2010-01
- Volume
- 51
- Issue
- 1
- Pages
- 246-254
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2977522
- OpenAlex
- W2160775206
- Cited by
- 430
- References
- 36
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 28 · 2023: 27 · 2022: 25 · 2021: 35 · 2020: 38 · 2019: 35 · 2018: 30 · 2017: 30 · 2016: 26 · 2015: 28 · 2014: 25 · 2013: 27 · 2012: 20
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01 AA-12916, R01AA012916)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070195)
- National Center for Research Resources (P20RR021940, P20RR016475)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Keywords
- acetaminophen hepatotoxicity, glutathione, N-acetylcysteine, acetaminophen overdose, N-acetyl-p-benzoquinone imine, peroxynitrite, DNA fragmentation, mitochondrial glutathione, ATP levels, mitochondrial bioenergetics, liver injury prevention, treatment delay
- MeSH terms
- Acetaminophen, Acetylcysteine, Animals, Energy Metabolism, Glutathione, Male, Mice, Inbred C3H, Mitochondria, Liver, Up-Regulation, Reactive Oxygen Species, Peroxynitrous Acid, Mice, Chemical and Drug Induced Liver Injury, Drug Overdose
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