| HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. | |
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MedLine Citation:
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PMID: 21319200 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. In the last four decades much progress has been made in our understanding of APAP-induced liver injury through rodent studies. However, some differences exist in the time course of injury between rodents and humans. To study the mechanism of APAP hepatotoxicity in humans, a human-relevant in vitro system is needed. Here we present evidence that the cell line HepaRG is a useful human model for the study of APAP-induced liver injury. Exposure of HepaRG cells to APAP at several concentrations resulted in glutathione depletion, APAP-protein adduct formation, mitochondrial oxidant stress and peroxynitrite formation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase (LDH) release. Importantly, the time course of LDH release resembled the increase in plasma aminotransferase activity seen in humans following APAP overdose. Based on propidium iodide uptake and cell morphology, the majority of the injury occurred within clusters of hepatocyte-like cells. The progression of injury in these cells involved mitochondrial reactive oxygen and reactive nitrogen formation. APAP did not increase caspase activity above untreated control values and a pancaspase inhibitor did not protect against APAP-induced cell injury. CONCLUSION: These data suggest that key mechanistic features of APAP-induced cell death are the same in human HepaRG cells, rodent in vivo models, and primary cultured mouse hepatocytes. Thus, HepaRG cells are a useful model to study mechanisms of APAP hepatotoxicity in humans. |
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Authors:
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Mitchell R McGill; Hui-Min Yan; Anup Ramachandran; Gordon J Murray; Douglas E Rollins; Hartmut Jaeschke |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-02-11 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 53 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-04 Completed Date: 2011-05-12 Revised Date: 2012-05-14 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 974-82 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 American Association for the Study of Liver Diseases. |
Affiliation:
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetaminophen
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metabolism,
toxicity* Animals Cell Line, Tumor Cysteine / metabolism Drug-Induced Liver Injury* / metabolism, pathology Female Glutathione / metabolism Hep G2 Cells Humans Mice Models, Biological Necrosis Reactive Nitrogen Species / metabolism Reactive Oxygen Species |
| Grant Support | |
ID/Acronym/Agency:
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P20 RR 021940/RR/NCRR NIH HHS; P20 RR016475/RR/NCRR NIH HHS; R01 AA012916/AA/NIAAA NIH HHS; R01 AA012916-08/AA/NIAAA NIH HHS; R01 AA12916/AA/NIAAA NIH HHS; R01 DK070195/DK/NIDDK NIH HHS; R01 DK070195-05/DK/NIDDK NIH HHS; R01 DK070195-05S1/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Reactive Nitrogen Species; 0/Reactive Oxygen Species; 103-90-2/Acetaminophen; 52-90-4/Cysteine; 70-18-8/Glutathione |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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