Gao Ling, Yin Huiyong, Milne Ginger L, Porter Ned A, Morrow Jason D
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
J Biol Chem. 2006 May 19;281(20):14092-9. doi: 10.1074/jbc.M601035200. Epub 2006 Mar 28.
Eicosapentaenoic acid (EPA, C20:5, omega-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 omega-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 microg/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.
二十碳五烯酸（EPA，C20:5，ω-3）是鱼油中含量最丰富的多不饱和脂肪酸（PUFA）。最近的研究表明，鱼油的有益作用部分归因于ω-3多不饱和脂肪酸产生的各种自由基生成的非酶促生物活性氧化产物，尽管尚未确定造成这些作用的具体分子种类。我们的研究小组之前报道过，促炎性前列腺素F2样化合物，即F2-异前列腺素（IsoPs），是体内由花生四烯酸的自由基催化过氧化作用产生的，并且是该多不饱和脂肪酸氧化的主要产物之一。基于这些观察结果，我们质疑F2-异前列腺素样化合物（F3-异前列腺素）是否在体内由EPA氧化形成。体外EPA氧化产生了一系列化合物，通过多种化学和质谱方法在结构上确定它们为F3-异前列腺素。生成的量极大（高达8.7 + 1.0微克/毫克EPA），且高于花生四烯酸产生的F2-异前列腺素水平。然后我们检测了小鼠体内F3-异前列腺素的形成。在基线时，心脏等组织中的F3-异前列腺素水平几乎检测不到，但给动物补充EPA后，其含量显著增加，最高可达27.4 + 5.6纳克/克心脏。有趣的是，补充EPA还使促炎性花生四烯酸衍生的F2-异前列腺素水平显著降低，降幅高达64%（p < 0.05）。我们的研究首次提供了证据，确定F3-异前列腺素是体内产生的EPA新型氧化产物。对F3-异前列腺素形成的生物学后果的进一步了解可能为EPA的心脏保护机制提供有价值的见解。
