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J. Biol. Chem., Vol. 281, Issue 20, 14092-14099, May 19, 2006

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Formation of F-ring Isoprostane-like Compounds (F₃-Isoprostanes) in Vivo from Eicosapentaenoic Acid^*

Ling Gao, Huiyong Yin, Ginger L. Milne, 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

Eicosapentaenoic acid (EPA, C20:5, -3) is the most abundant polyunsaturated fatty acid (PUFA) in fish oil. Recent studies suggest that the beneficial effects of fish oil are due, in part, to the generation of various free radical-generated non-enzymatic bioactive oxidation products from -3 PUFAs, although the specific molecular species responsible for these effects have not been identified. Our research group has previously reported that pro-inflammatory prostaglandin F₂-like compounds, termed F₂-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 F₂-IsoP-like compounds (F₃-IsoPs) are formed from the oxidation of EPA in vivo. Oxidation of EPA in vitro yielded a series of compounds that were structurally established to be F₃-IsoPs using a number of chemical and mass spectrometric approaches. The amounts formed were extremely large (up to 8.7 + 1.0 µg/mg EPA) and greater than levels of F₂-IsoPs generated from arachidonic acid. We then examined the formation of F₃-IsoPs in vivo in mice. Levels of F₃-IsoPs in tissues such as heart are virtually undetectable at baseline, but supplementation of animals with EPA markedly increases quantities up to 27.4 + 5.6 ng/g of heart. Interestingly, EPA supplementation also markedly reduced levels of pro-inflammatory arachidonate-derived F₂-IsoPs by up to 64% (p < 0.05). Our studies provide the first evidence that identify F₃-IsoPs as novel oxidation products of EPA that are generated in vivo. Further understanding of the biological consequences of F₃-IsoP formation may provide valuable insights into the cardioprotective mechanism of EPA.

Received for publication, February 2, 2006 , and in revised form, March 16, 2006.

^* This work was supported by National Institutes of Health Grants GM15431, ES31125, RR00096, DK48831, and CA77839. 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. Tel.: 615-343-1124; Fax: 615-322-3669; E-mail: jason.morrow{at}vanderbilt.edu.

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