Document Detail

Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells.
MedLine Citation:
PMID:  14684755     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Polyunsaturated fatty acids such as linoleic acid are well known dietary lipids that may be atherogenic by activating vascular endothelial cells. In the liver, fatty acids can be metabolized by cytochrome P450 (CYP) enzymes, but little is known about the role of these enzymes in the vascular endothelium. CYP 2C9 is involved in linoleic acid epoxygenation, and the major product of this reaction is leukotoxin (LTX). We investigated the role of CYP-mediated mechanisms of linoleic acid metabolism in endothelial cell activation by examining the effects of linoleic acid or its oxidized metabolites such as LTX and leukotoxin diol (LTD). METHODS: The effect of linoleic acid on CYP 2C9 gene expression was studied by RT-PCR. Oxidative stress was monitored by measuring DCF fluorescence and intracellular glutathione levels, and electrophoretic mobility shift assay was carried out to study the activation of oxidative stress sensitive transcription factors. Analysis of oxidized lipids was carried out by liquid chromatography/mass spectrometry. RESULTS: Linoleic acid treatment for six hours increased the expression of CYP 2C9 in endothelial cells. Linoleic acid-mediated increase in oxidative stress and activation of AP-1 were blocked by sulfaphenazole, a specific inhibitor of CYP 2C9. The linoleic acid metabolites LTX and LTD increased oxidative stress and activation of transcription factors only at high concentrations. CONCLUSION: Our data show that CYP 2C9 plays a key role in linoleic acid-induced oxidative stress and subsequent proinflammatory events in vascular endothelial cells by possibly causing superoxide generation through uncoupling processes.
Saraswathi Viswanathan; Bruce D Hammock; John W Newman; Purushothaman Meerarani; Michal Toborek; Bernhard Hennig
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of the American College of Nutrition     Volume:  22     ISSN:  0731-5724     ISO Abbreviation:  J Am Coll Nutr     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-19     Completed Date:  2006-04-26     Revised Date:  2008-06-23    
Medline Journal Info:
Nlm Unique ID:  8215879     Medline TA:  J Am Coll Nutr     Country:  United States    
Other Details:
Languages:  eng     Pagination:  502-10     Citation Subset:  IM    
Molecular and Cell Nutrition Laboratory, College of Agriculture, University of Kentucky, Lexington, KY 40546-0215, USA.
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MeSH Terms
Aryl Hydrocarbon Hydroxylases / metabolism*
Dose-Response Relationship, Immunologic
Electrophoretic Mobility Shift Assay
Endothelial Cells / drug effects,  metabolism*
Endothelium, Vascular / cytology,  metabolism*
Exotoxins / metabolism,  pharmacology
Gas Chromatography-Mass Spectrometry
Gene Expression Regulation / drug effects
Glutathione / metabolism
Immunosuppressive Agents / pharmacology
Inflammation Mediators / metabolism*
Linoleic Acid / metabolism*,  pharmacology*
NF-kappa B / drug effects,  metabolism
Oxidative Stress / drug effects
Pulmonary Artery / cytology
Reactive Oxygen Species / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Stearic Acids / metabolism,  pharmacology
Transcription Factor AP-1 / drug effects,  metabolism
Umbilical Veins / cytology
Grant Support
Reg. No./Substance:
0/9,10-dihydroxy-12-octadecenoic acid; 0/Exotoxins; 0/Immunosuppressive Agents; 0/Inflammation Mediators; 0/NF-kappa B; 0/Reactive Oxygen Species; 0/Stearic Acids; 0/Transcription Factor AP-1; 0/leukotoxin; 2197-37-7/Linoleic Acid; 70-18-8/Glutathione; EC Hydrocarbon Hydroxylases; EC protein, human

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