ArticleToxicology and applied pharmacology2014
Mechanisms of acetaminophen-induced cell death in primary human hepatocytes.
Article in Toxicology and applied pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 154 papers.
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Who cites it
154 citing papers in PubMed, 245 citations in OpenAlex.
- In Vitro Three-Dimensional Human Liver Model for Drug-Induced Liver and Bile Duct Injury Prediction.Toxics · 2026Article
- Computational integration of in vivo single cell and in vitro bulk transcriptomics across 236 human and mouse datasets differentiates physiological versus non-physiological hepatic cell lines for hepatotoxicity screening.Toxicological sciences : an official journal of the Society of Toxicology · 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
- Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.The American journal of pathology · 2026Article
- Reactive oxygen species and peroxynitrite in acetaminophen-induced liver injury: Lipid peroxidation and ferroptosis-like cell death.Ferroptosis and oxidative stress · 2026Article
- R-α-Lipoic Acid Attenuates Acetaminophen-Induced Acute Liver Injury by Reducing Oxidative Stress, Inflammation, and Mitochondrial Damage in Mice.Drug design, development and therapy · 2026Article
- Article
- Are New Approach Methodologies (NAMs) the Holy Grail of toxicology?Toxicological sciences : an official journal of the Society of Toxicology · 2025Review
- Pristimerin Dampens Acetaminophen-Induced Hepatotoxicity; The Role of NF-κB/iNOS/COX-II/Cytokines, PI3K/AKT, and BAX/BCL-2/Caspase-3 Signaling Pathways.Pharmaceutics · 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
- Natural Products That Protect Against Acetaminophen Hepatotoxicity: A Call for Increased Rigor in Preclinical Studies of Dietary Supplements.Journal of dietary supplements · 2025Review
- Limitations of acetaminophen as a reference hepatotoxin for the evaluation of in vitro liver models.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- The multiple mechanisms and modes of cell death after acetaminophen overdose.Exploration of digestive diseases · 2025Article
- Delayed treatment with hydro-ethanolic extract ofPharmaceutical science advances · 2024Article
- Three consecutive cases of acute liver failure in young women due to acetaminophen overdose: insights into Japanese social issues and transplantation landscape.Clinical journal of gastroenterology · 2024Article
- Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.Biochemical pharmacology · 2024Review
- The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis.Biomolecules & therapeutics · 2024Article
- The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- The Discovery of Gut Microbial Metabolites as Modulators of Host Susceptibility to Acetaminophen-Induced Hepatotoxicity.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
94 more citing papers are in PubMed but not listed here.
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7 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledAcetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5mM, 10mM or 20mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24h and 48h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6h after APAP and a partial protection when given at 15 h.
conclusionThese data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic.
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