Document Detail


Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis in cultured mouse hepatocytes.
MedLine Citation:
PMID:  12085349     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hidenari Nagai; Katsuhiko Matsumaru; Guoping Feng; Neil Kaplowitz
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  36     ISSN:  0270-9139     ISO Abbreviation:  Hepatology     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-06-26     Completed Date:  2002-07-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  55-64     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
Acetaminophen / 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:
P01 DK 48522/DK/NIDDK NIH HHS; P50 AA 11999/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
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

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