ArticleToxicology and applied pharmacology2020
4-methylpyrazole protects against acetaminophen-induced acute kidney injury.
Article in Toxicology and applied pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 65 citations in OpenAlex.
- Rational design of pyrazole-oxime hybrids as dual-targeting agents for glioma and breast cancer brain metastasis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Dose- and Organ-Specific Dual Effects of MitoTempo in Paracetamol-Induced Hepatorenal Toxicity in Mice.Biomolecules · 2026Article
- Differential effects on acetaminophen-induced nephrotoxicity and liver injury following modulation of glutathione resynthesis.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2026Article
- Alterations in Adenylate Nucleotide Metabolism and Associated Lipid Peroxidation and Protein Oxidative Damage in Rat Kidneys Under Combined Acetaminophen Toxicity and Protein Deficiency.Antioxidants (Basel, Switzerland) · 2026Article
- Protective effects ofFrontiers in toxicology · 2026Article
- Mechanistic insights into hepatic cell type-specific contributions to acetaminophen-induced acute liver injury.World journal of gastroenterology · 2025Review
- A multi-omics landscape of programmed cell death in acetaminophen-induced acute kidney injury.Renal failure · 2025Article
- Can Acetaminophen be Used as a Chemotherapeutic Agent in the Kidney?Journal of biochemical and molecular toxicology · 2025Article
- High-dose acetaminophen does not acutely compromise blood-brain barrier permeability in mice.Metabolic brain disease · 2025Article
- 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
- NAPQI is absent in the mouse brain after sub-hepatotoxic and hepatotoxic doses of acetaminophen.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Dihydromyricetin Alleviated Acetaminophen-Induced Acute Kidney Injury via Nrf2-Dependent Anti-Oxidative and Anti-Inflammatory Effects.International journal of molecular sciences · 2025Article
- Preventive and therapeutic effects of cepharanthine on acetaminophen-induced acute liver and kidney injury in male laboratory mice.Gastroenterology and hepatology from bed to bench · 2025Article
- Magnesium hydride protects against acetaminophen-induced acute kidney injury by inhibiting TXNIP/NLRP3/nf-κb pathway.Renal failure · 2024Article
- Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.Biochemical pharmacology · 2024Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Good Cells Go Bad: Immune Dysregulation in the Transition from Acute Liver Injury to Liver Failure After Acetaminophen Overdose.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- 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
- Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.Annual review of pathology · 2024Review
- High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.The Journal of pharmacology and experimental therapeutics · 2024Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Acetaminophen (APAP) hepatotoxicity is the most common cause of acute liver failure in the United States, and while a significant percentage of APAP overdose patients develop kidney injury, molecular mechanisms involved in APAP-induced nephrotoxicity are relatively unknown. We have shown that 4-methylpyrazole (4MP, Fomepizole) protects against APAP-induced liver injury by inhibiting reactive metabolite formation through Cyp2E1, and analysis of data from APAP overdose patients indicated that kidney dysfunction strongly correlated with severe liver injury. Since Cyp2E1 is also expressed in the kidney, this study explored protection by 4MP against APAP-induced nephrotoxicity. Male C57BL/6 J mice were treated with either 300 or 600 mg/kg APAP with or without 4MP for 2, 6 or 24 h, followed by measurement of APAP metabolism and tissue injury. Interestingly, levels of APAP and its non-oxidative metabolites were significantly higher in kidneys when compared to the liver. APAP-protein adducts were present in both tissues within 2 h, but were absent in kidney mitochondria, unlike in the liver. While GSH depletion was seen in both tissues, activation of c-jun N-terminal kinase and its translocation to the mitochondria, which is a critical feature of APAP-induced liver injury, was not detected in the kidney. Treatment with 4MP attenuated APAP oxidative metabolite generation, GSH depletion as well as kidney injury indicating its potential use in protection against APAP-induced nephrotoxicity. In conclusion, since reactive metabolite formation seems to be common in both liver and kidney, 4MP mediated inhibition of Cyp2E1 protects against APAP-induced nephrotoxicity. However, downstream mechanisms of APAP-induced nephrotoxicity seem distinct from the liver.
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