| Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis in cultured mouse hepatocytes. | |
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MedLine Citation:
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PMID: 12085349 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The effect of reduced glutathione (GSH) depletion by acetaminophen (APAP), diethylmaleate (DEM), or phorone on the mode of cell death and susceptibility to tumor necrosis factor (TNF)-induced cell death was studied in cultured mouse hepatocytes. Dose-dependent necrosis was the exclusive mode of cell death with APAP alone, but the addition of TNF-alpha induced a switch to about half apoptosis without changing total loss of viability. This effect was seen at 1 and 5 mmol/L but was inhibited at 10 and 20 mmol/L APAP. The switch to apoptosis was associated with increased caspase activities, release of cytochrome c, and DNA laddering and was inhibited by caspase inhibitors. DEM and phorone also induced dose-dependent necrosis. Treatment with TNF-alpha under these conditions lead to incremental cell death in the form of apoptosis at 0.25 and 0.5 mmol/L DEM and 0.1 and 0.2 mmol/L phorone. At 1.0 and 2.0 mmol/L DEM and 0.5 mmol/L phorone, 90% to 100% necrosis was observed with resistance to TNF-alpha effects. The apoptosis with TNF-alpha plus DEM was confirmed by DNA laddering and inhibition by caspase inhibitors. However, in the presence of caspase inhibitors, the increment in cell death induced by TNF-alpha persisted as an increase in necrosis. A combination of antioxidants, vitamin E, and butylated hydroxytoluene (BHT) markedly inhibited necrosis induced by APAP or DEM alone, but the sensitization to TNF-alpha-induced apoptosis was unaffected. GSH monoethylester (GSH-EE) protected against necrosis and apoptosis. In conclusion, depletion of GSH by APAP, DEM, or phorone causes oxidative stress-induced necrosis and sensitizes to an oxidative stress independent TNF-alpha-induced apoptosis. |
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Authors:
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Hidenari Nagai; Katsuhiko Matsumaru; Guoping Feng; Neil Kaplowitz |
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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: Hepatology (Baltimore, Md.) Volume: 36 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-06-26 Completed Date: 2002-07-23 Revised Date: 2007-11-14 |
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: 55-64 Citation Subset: IM |
Affiliation:
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USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic and Pancreatic Disease, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetaminophen
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pharmacology Animals Antioxidants / pharmacology Apoptosis / drug effects* Butylated Hydroxytoluene / pharmacology Caspases / antagonists & inhibitors, metabolism Cells, Cultured Cytochrome c Group / metabolism DNA Fragmentation Glutathione / antagonists & inhibitors*, metabolism* Hepatocytes / cytology* Ketones / pharmacology Maleates / pharmacology Mice Mice, Inbred C57BL NF-kappa B / pharmacology Necrosis Oxidative Stress Tumor Necrosis Factor-alpha / pharmacology* Vitamin E / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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P01 DK 48522/DK/NIDDK NIH HHS; P50 AA 11999/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Cytochrome c Group; 0/Ketones; 0/Maleates; 0/NF-kappa B; 0/Tumor Necrosis Factor-alpha; 103-90-2/Acetaminophen; 128-37-0/Butylated Hydroxytoluene; 1406-18-4/Vitamin E; 141-05-9/diethyl maleate; 504-20-1/phorone; 70-18-8/Glutathione; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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