Document Detail


Ethanol and arachidonic acid produce toxicity in hepatocytes from pyrazole-treated rats with high levels of CYP2E1.
MedLine Citation:
PMID:  10718635     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ethanol and polyunsaturated fatty acids such as arachidonic acid were shown to be toxic and cause apoptosis in HepG2 cells which express CYP2E1 but not in control HepG2 cell lines. The goal of the current study was to extend the observations made with the HepG2 cells to non-transformed, intact hepatocytes. Rats were treated with pyrazole to increase CYP2E1 levels, hepatocytes were isolated and placed into culture and treated for varying time points with ethanol or arachidonic acid. Comparisons were made to hepatocytes from saline-treated rats, with low CYP2E1 content. Incubation with ethanol (100 mM) or especially arachidonic acid (60 microM) resulted in loss of viability of hepatocytes from the pyrazole-treated rats, without any effect on the hepatocytes from the saline-treated rats. The toxicity appeared to be apoptotic in nature and was prevented by diallyldisulfide, an inhibitor of CYP2E1. Toxicity was reduced by trolox, an antioxidant. The treatment with ethanol or arachidonic acid resulted in release of cytochrome c into the cytosol fraction, and activation of caspase 3 (but not caspase 1) in hepatocytes from the pyrazole-treated rats but not hepatocytes from the saline-treated rats. The activation of caspase 3 was prevented by diallyldisulfide, by trolox, and by DEVD-fmk. The latter also prevented the toxicity produced by ethanol or arachidonic acid. These results extend previous observations found with HepG2 cells expressing CYP2E1 to intact hepatocytes and suggest that release of cytochrome c and activation of caspase 3 play a role in the overall pathway by which CYP2E1 contributes towards the hepatotoxic actions of ethanol and polyunsaturated fatty acids.
Authors:
D Wu; A I Cederbaum
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular and cellular biochemistry     Volume:  204     ISSN:  0300-8177     ISO Abbreviation:  Mol. Cell. Biochem.     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-04-11     Completed Date:  2000-04-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0364456     Medline TA:  Mol Cell Biochem     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  157-67     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Arachidonic Acid / pharmacology*
Caspases / metabolism
Cells, Cultured
Chromans / pharmacology
Cytochrome P-450 CYP2E1 / metabolism*
Cytochrome c Group / metabolism
Cytosol / metabolism
Disulfides / pharmacology
Enzyme Activation
Ethanol / pharmacology*
Flow Cytometry
Liver / cytology,  drug effects*,  enzymology
Male
Oligopeptides / pharmacology
Oxidative Stress
Pyrazoles / pharmacology
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
AA03312/AA/NIAAA NIH HHS; AA06610/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Chromans; 0/Cytochrome c Group; 0/Disulfides; 0/Oligopeptides; 0/Pyrazoles; 0/benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; 288-13-1/pyrazole; 506-32-1/Arachidonic Acid; 56305-04-5/6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; 64-17-5/Ethanol; EC 1.14.14.1/Cytochrome P-450 CYP2E1; EC 3.4.22.-/Caspases

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