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J Biol Chem, Vol. 274, Issue 23, 16235-16241, June 4, 1999

Nitrogen Dioxide Induces cis-trans-Isomerization of Arachidonic Acid within Cellular Phospholipids
DETECTION OF TRANS-ARACHIDONIC ACIDS IN VIVO

Houli Jiang, Nathan Kruger, Debarshi Rana Lahiri, Dairong Wang, Jean-Michel Vatèle^§, and Michael Balazy

From the  Department of Pharmacology, New York Medical College, Valhalla, New York 10595 and the ^§ Laboratoire de Chimie Organique 1, Université Claude Bernard, 69622 Villeurbanne Cédex, France

Oxygen free radicals oxidize arachidonic acid to a complex mixture of metabolites termed isoeicosanoids that share structural similarity to enzymatically derived eicosanoids. However, little is known about oxidations of arachidonic acid mediated by reactive radical nitrogen oxides. We have studied the reaction of arachidonic acid with NO₂, a free radical generated by nitric oxide and nitrite oxidations. A major group of products appeared to be a mixture of arachidonic acid isomers having one trans-bond and three cis-double bonds. We have termed these new products trans-arachidonic acids. These isomers were chromatographically distinct from arachidonic acid and produced mass spectra that were nearly identical with mass spectra of arachidonic acid. The lack of ultraviolet absorbance above 205 nm and the similarity of mass spectra of dimethyloxazoline derivatives suggested that the trans-bond was not conjugated with any of the cis-bonds, and the C=C bonds were located at carbons 5, 8, 11, and 14. Further identification was based on comparison of chromatographic properties with synthetic standards and revealed that NO₂ generated 14-trans-eicosatetraenoic acid and a mixture containing 11-trans-, 8-trans-, and 5-trans-eicosatetraenoic acids. Exposure of human platelets to submicromolar levels of NO₂ resulted in a dose-dependent formation of 14-trans-eicosatetraenoic acid and other isomers within platelet glycerophospholipids. Using a sensitive isotopic dilution assay we detected trans-arachidonic acids in human plasma (50.3 ± 10 ng/ml) and urine (122 ± 50 pg/ml). We proposed a mechanism of arachidonic acid isomerization that involves a reversible attachment of NO₂ to a double bond with formation of a nitroarachidonyl radical. Thus, free radical processes mediated by NO₂ lead to generation of trans-arachidonic acid isomers, including biologically active 14-trans-eicosatetraenoic acid, within membrane phospholipids from which they can be released and excreted into urine.

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