| Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: effects of Ca(2+)-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. | |
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MedLine Citation:
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PMID: 1310169 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hepatotoxic alkylation of mouse liver cells by acetaminophen is characterized by an early loss of ion regulation, accumulation of Ca2+ in the nucleus, and fragmentation of DNA in vitro and in vivo. Acetaminophen-induced DNA cleavage is accompanied by the formation of a "ladder" of DNA fragments characteristic of Ca(2+)-mediated endonuclease activation. These events unfold well in advance of cytotoxicity and the development of necrosis. The present study utilized cultured mouse hepatocytes and mechanistic probes to test whether DNA fragmentation and cell death might be related in a "cause-and-effect" manner. Cells were isolated by collagenase perfusion, cultured in Williams' E medium for 22-26 hr, and exposed to acetaminophen. Aurintricarboxylic acid, a general Ca(2+)-endonuclease inhibitor, and EGTA, a chelator of Ca2+ required for endonuclease activation, significantly decreased DNA fragmentation at 6 and 12 hr and virtually abolished cytotoxicity. N-Acetylcysteine also eliminated DNA fragmentation and cytotoxicity. 3-Aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase-stimulated DNA repair, failed to alter the amount of DNA fragmentation at 6 hr but substantially increased acetaminophen cytotoxicity in hepatocytes at 12 hr. With the exception of when DNA repair was inhibited by 3-aminobenzamide, Ca2+ accumulation in the nucleus, DNA fragmentation, and hepatocyte death varied consistently and predictably with one another. Collectively, these findings suggest that unrepaired damage to DNA contributes to acetaminophen-induced cell death in vivo and may play a role in necrosis in vivo. |
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Authors:
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W Shen; L M Kamendulis; S D Ray; G B Corcoran |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 112 ISSN: 0041-008X ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 1992 Jan |
Date Detail:
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Created Date: 1992-02-27 Completed Date: 1992-02-27 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 32-40 Citation Subset: IM |
Affiliation:
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Toxicology Program, College of Pharmacy, University of New Mexico, Albuquerque 87131-1066. |
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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adverse effects* Acetylcysteine / pharmacology Adenosine Diphosphate / metabolism Animals Aurintricarboxylic Acid / pharmacology Benzamides / pharmacology Calcium / metabolism*, pharmacology Cell Death / drug effects, physiology Cell Nucleus / drug effects, metabolism Cells, Cultured DNA / drug effects*, metabolism DNA Damage* DNA Repair* Egtazic Acid / pharmacology Endonucleases / drug effects, metabolism*, physiology Enzyme Activation / drug effects Glutathione / metabolism* Liver / cytology*, drug effects Male Mice |
| Grant Support | |
ID/Acronym/Agency:
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GM 41564/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 103-90-2/Acetaminophen; 3544-24-9/3-aminobenzamide; 4431-00-9/Aurintricarboxylic Acid; 58-64-0/Adenosine Diphosphate; 616-91-1/Acetylcysteine; 67-42-5/Egtazic Acid; 70-18-8/Glutathione; 7440-70-2/Calcium; 9007-49-2/DNA; EC 3.1.-/Endonucleases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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