ArticleHuman & experimental toxicology2018
4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes.
Article in Human & experimental toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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The trial behind it
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Who cites it
63 citing papers in PubMed, 111 citations in OpenAlex.
- Effects of Fomepizole on Acetaminophen Oxidative Metabolism: A Randomized, Crossover Study in Human Volunteers.Clinical pharmacology and therapeutics · 2026Trial
- The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers.Journal of medical toxicology : official journal of the American College of Medical Toxicology · 2020Trial
- Article
- Hepatic p38γ exacerbates acetaminophen‑induced acute liver injury via PI3K/Akt‑dependent mechanisms.International journal of molecular medicine · 2026Article
- Panthenol Protects Against Oxidative Stress and Liver Fibrosis in Cholestasis in Association with Increased Coenzyme A Biosynthesis.International journal of molecular sciences · 2026Article
- Imaging bioactive lipid isomers in acetaminophen-induced liver injury using nano-DESI tandem MS.Journal of lipid research · 2026Article
- An integrative approach to detecting potential blood-based biomarkers of cognitive frailty.The journal of nutrition, health & aging · 2026Observational
- Reactive oxygen species and peroxynitrite in acetaminophen-induced liver injury: Lipid peroxidation and ferroptosis-like cell death.Ferroptosis and oxidative stress · 2026Article
- Are New Approach Methodologies (NAMs) the Holy Grail of toxicology?Toxicological sciences : an official journal of the Society of Toxicology · 2025Review
- Article
- 4-Methylpyrazole-mediated inhibition of cytochrome P450 2E1 protects renal epithelial cells, but not bladder cancer cells, from cisplatin toxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Mixed lineage kinase domain-like protein deficiency exacerbates early injury in a mouse model of acetaminophen hepatotoxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Acetaminophen should be a critical reference hepatotoxin for evaluating human-relevant in vitro models.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Article
- A weekly 4-methylpyrazole treatment attenuates the development of non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in male mice: Role of JNK.European journal of clinical investigation · 2025Article
- Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.Biochemical pharmacology · 2024Review
- Targeting chronic liver diseases: Molecular markers, drug delivery strategies and future perspectives.International journal of pharmaceutics · 2024Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose.Molecular medicine (Cambridge, Mass.) · 2024Article
- Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.Toxicological sciences : an official journal of the Society of Toxicology · 2024Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Liver injury due to acetaminophen (APAP) overdose is the major cause of acute liver failure in the United States. While treatment with N-acetylcysteine is the current standard of care for APAP overdose, anecdotal evidence suggests that administration of 4-methylpyrazole (4MP) may be beneficial in the clinic. The objective of the current study was to examine the protective effect of 4MP and its mechanism of action. Male C57BL/6J mice were co-treated with 300 mg/kg of APAP and 50 mg/kg of 4MP. The severe liver injury induced by APAP at 6 h as indicated by elevated plasma alanine aminotransferase activities, centrilobular necrosis, and nuclear DNA fragmentation was almost completely eliminated by 4MP. In addition, 4MP largely prevented APAP-induced activation of c-Jun N-terminal kinase (JNK), mitochondrial translocation of phospho-JNK and Bax, and the release of mitochondrial intermembrane proteins. Importantly, 4MP inhibited the generation of APAP protein adducts and formation of APAP-glutathione (GSH) conjugates and attenuated the depletion of the hepatic GSH content. These findings are relevant to humans because 4MP also prevented APAP-induced cell death in primary human hepatocytes. In conclusion, early treatment with 4MP can completely prevent liver injury after APAP overdose by inhibiting cytochrome P450 and preventing generation of the reactive metabolite.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.