Formation of highly reactive cyclopentenone isoprostane compounds (A3/J3-isoprostanes) in vivo from eicosapentaenoic acid
Formation of highly reactive cyclopentenone isoprostane compounds (A3/J3-isoprostanes) in vivo from eicosapentaenoic acid
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DOI：
10.1074/jbc.m800122200
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发表时间：
2008-05-02
影响因子：
4.8
通讯作者：
Morrow, Jason D.
中科院分区：
文献类型：
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作者：
Brooks, Joshua D.;Milne, Ginger L.;Morrow, Jason D.
已知海洋鱼油中发现的欧米茄-3（omega-3）多不饱和脂肪酸（PUFA）可抑制与多种疾病相关的炎症。二十碳五烯酸（EPA）是鱼油中最丰富的ω-3脂肪酸之一，但EPA发挥其有益作用的机制尚不清楚。然而，最近的研究表明，氧化EPA，而不是天然EPA，具有抗动脉粥样硬化，抗炎和抗增殖作用。到目前为止，很少有研究调查EPA氧化产物是负责这种生物活性。我们的研究小组先前报道了抗炎的前列腺素A（2）样和前列腺素J（2）样化合物，称为A（2）/J（2）-异前列腺烷（IsoPs），在体内由花生四烯酸的自由基催化的过氧化产生，并且是由这种PUFA氧化产生的主要产物之一。基于这些观察结果，我们质疑环戊烯酮-IsoP化合物是否由EPA在体内的氧化形成。在此，我们报告了环戊烯酮-IsoP分子的形成，称为A（3）/J（3）-IsoPs，在体外和体内从EPA过氧化反应中大量形成。采用化学方法结合气相色谱/质谱（GC/MS）和液相色谱/质谱（LC/MS）对这些化合物进行了结构表征，确定其为A（3）/J（3）-IsoPs。我们发现，这些分子的水平随着EPA的体外氧化增加了200倍，从0.8 +/- 0.4 ng/mg EPA的基础水平增加到36小时后的196 +/- 23 ng/mg EPA。我们还在EPA喂养大鼠的新鲜肝组织中检测到大量这些化合物，基础水平为19 +/- 2 ng/g组织。在氧化应激环境中，体内含量增加至102 +/- 15 ng/g组织。这些研究首次明确地表征了新型的、高反应性的A/J环IsoP化合物，这些化合物在体内从EPA的氧化中大量形成。
Omega-3 (omega-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 omega-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 A(2)-like and prostaglandin J(2)-like compounds, termed A(2)/J(2)-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 A(3)/J(3)-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 A(3)/J(3)-IsoPs. We found that levels of these molecules increase similar to 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.