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J. Biol. Chem., Vol. 283, Issue 18, 12043-12055, May 2, 2008

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Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A₃/J₃-Isoprostanes) in Vivo from Eicosapentaenoic Acid^*

Joshua D. Brooks, Ginger L. Milne, Huiyong Yin, Stephanie C. Sanchez, Ned A. Porter, and Jason D. Morrow¹

From the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology and the Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232

Omega-3 (-3) polyunsaturated fatty acids (PUFAs) found in marine fish oils are known to suppress inflammation associated with a wide variety of diseases. Eicosapentaenoic acid (EPA) is one of the most abundant -3 fatty acids in fish oil, but the mechanism(s) by which EPA exerts its beneficial effects is unknown. Recent studies, however, have demonstrated that oxidized EPA, rather than native EPA, possesses anti-atherosclerotic, anti-inflammatory, and anti-proliferative effects. Very few studies to date have investigated which EPA oxidation products are responsible for this bioactivity. Our research group has previously reported that anti-inflammatory prostaglandin A₂-like and prostaglandin J₂-like compounds, termed A₂/J₂-isoprostanes (IsoPs), are produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid and represent one of the major products resulting from the oxidation of this PUFA. Based on these observations, we questioned whether cyclopentenone-IsoP compounds are formed from the oxidation of EPA in vivo. Herein, we report the formation of cyclopentenone-IsoP molecules, termed A₃/J₃-IsoPs, formed in abundance in vitro and in vivo from EPA peroxidation. Chemical approaches coupled with gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) were used to structurally characterize these compounds as A₃/J₃-IsoPs. We found that levels of these molecules increase 200-fold with oxidation of EPA in vitro from a basal level of 0.8 ± 0.4 ng/mg EPA to 196 ± 23 ng/mg EPA after 36 h. We also detected these compounds in significant amounts in fresh liver tissue from EPA-fed rats at basal levels of 19 ± 2 ng/g tissue. Amounts increased to 102 ± 15 ng/g tissue in vivo in settings of oxidative stress. These studies have, for the first time, definitively characterized novel, highly reactive A/J-ring IsoP compounds that form in abundance from the oxidation of EPA in vivo.

Received for publication, January 7, 2008 , and in revised form, February 4, 2008.

^* This work was supported by National Institutes of Health Grants GM15431, DK48831, and ES13125. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 532 RRB, 23^rd Ave. S. at Pierce Ave., Vanderbilt University, Nashville, TN 37232-6602. Tel.: 615-343-1124; Fax: 615-322-3669; E-mail: jason.morrow{at}vanderbilt.edu.

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