Delayed Treatment With 4-Methylpyrazole Protects Against Acetaminophen Hepatotoxicity in Mice by Inhibition of c-Jun n-Terminal Kinase
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Acetaminophen (APAP) overdose is the most common cause of hepatotoxicity and acute liver failure in the United States and many western countries. However, the only clinically approved antidote, N-acetylcysteine, has a limited therapeutic window. 4-Methylpyrazole (4MP) is an antidote for methanol and ethylene glycol poisoning, and we have recently shown that cotreatment of 4MP with APAP effectively prevents toxicity by inhibiting Cyp2E1. To evaluate if 4MP can be used therapeutically, C57BL/6J mice were treated with 300 mg/kg APAP followed by 50 mg/kg 4MP 90 min later (after the metabolism phase). In these experiments, 4MP significantly attenuated liver injury at 3, 6, and 24 h after APAP as shown by 80%-90% reduction in plasma alanine aminotransferase activities and reduced areas of necrosis. 4MP prevented c-Jun c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, and reduced mitochondrial oxidant stress and nuclear DNA fragmentation. 4MP also prevented JNK activation in other liver injury models. Molecular docking experiments showed that 4MP can bind to the ATP binding site of JNK. These data suggest that treatment with 4MP after the metabolism phase effectively prevents APAP-induced liver injury in the clinically relevant mouse model in vivo mainly through the inhibition of JNK activation. 4MP, a drug approved for human use, is as effective as N-acetylcysteine or can be even more effective in cases of severe overdoses with prolonged metabolism (600 mg/kg). 4MP acts on alternative therapeutic targets and thus may be a novel approach to treatment of APAP overdose in patients that complements N-acetylcysteine.
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Evidence for use of fomepizole in paracetamol overdose is primarily from animal models and small case series.
“The evidence for use of fomepizole in this context is primarily from animal models [113] and small case series [114,115].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [113]
Fomepizole can prevent activation of the JNK enzyme and resultant mitochondrial dysfunction.
“Secondly, it can also prevent the activation of the JNK enzyme and resultant mitochondrial dysfunction [112,113].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [113]
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Self-citation
- Authors
- Akakpo, J. Y., Ramachandran, A., Duan, L., Schaich, M. A., Jaeschke, M. W., Freudenthal, B. D., Ding, W.-X., Rumack, B. H., & Jaeschke, H.
- Affiliations
- Department of Pharmacology Toxicology & Therapeutics
- University of Kansas Medical Center (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Jaeschke, Hartmut
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-03-23
- Volume
- 170
- Issue
- 1
- Pages
- 57-68
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC6592188
- OpenAlex
- W2937650113
- Cited by
- 105
- References
- 64
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 17 · 2023: 17 · 2022: 20 · 2021: 13 · 2020: 18 · 2019: 4
- FWCI
- 13.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McNeil Consumer Health Care, Inc
- National Institutes of Health (R01 DK102142)
- National Institute of General Medical Sciences (P20 GM103549 and P30 GM118247)
- from the National
- NIH Predoctoral Fellowship
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- acetaminophen hepatotoxicity, 4-methylpyrazole, c-Jun N-terminal kinase, N-acetylcysteine, acute liver failure, mitochondrial translocation, DNA fragmentation, CYP2E1, molecular docking, drug overdose
- MeSH terms
- Fomepizole, Acetaminophen, Animals, Male, Mice, Inbred C57BL, Protein Binding, Protein Kinase Inhibitors, JNK Mitogen-Activated Protein Kinases, Chemical and Drug Induced Liver Injury, Time-to-Treatment, Molecular Docking Simulation
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