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Journal of the American College of Nutrition, Vol. 22, No. 6, 502-510 (2003)
Published by the American College of Nutrition

Original Research

Involvement of CYP 2C9 in Mediating the Proinflammatory Effects of Linoleic Acid in Vascular Endothelial Cells

Saraswathi Viswanathan, PhD, Bruce D. Hammock, PhD, John W. Newman, PhD, Purushothaman Meerarani, PhD, Michal Toborek, MD, PhD and Bernhard Hennig, PhD, FACN

Molecular and Cell Nutrition Laboratory, College of Agriculture (S.V., P.M., B.H.), USA
Department of Surgery (M.T.), University of Kentucky, Lexington, KY, 40546-0215, USA
Department of Entomology and UC Cancer Center (B.D.H., J.W.N.), University of California, Davis, CA, USA

Address reprint requests to: Bernhard Hennig, PhD, RD, FACN, Molecular and Cell Nutrition Laboratory, College of Agriculture, 213 Garrigus Building, University of Kentucky, Lexington, KY 40546-0215. E-mail: bhennig{at}uky.edu

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.

Key words: linoleic acid, CYP 2C9, leukotoxin, leukotoxin diol, oxidative stress

Abbreviations: CYP = cytochrome P450 • ROS = reactive oxygen species • LTX = leukotoxin • LTD = leukotoxin diol • LA = linoleic acid • H2DCF-DA = Dichlorodihydrofluorescein diacetate • MnTMPyP = [Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride] • AP-1 = activator protein 1 • NF-{kappa}B = nuclear factor {kappa}B




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