Department of Chemistry, Case Western Reserve University, 2074 Adelbert Road, Millis 212, Cleveland, Ohio 44106, USA.
Chem Res Toxicol. 2010 Mar 15;23(3):516-27. doi: 10.1021/tx9002484.
Often guided by analogy with nonphospholipid products from oxidative cleavage of polyunsaturated fatty acids, we previously identified a variety of biologically active oxidatively truncated phospholipids. Previously, 4,5-epoxy-2(E)-decenal (4,5-EDE) was found to be produced by oxidative cleavage of 13-(S)-hydroperoxy-9,11-(Z,E)-octadeca-dienoic acid (13-HPODE). 4,5-EDE reacts with deoxy-adenosine (dAdo) and deoxy-guanosine (dGuo) to form mutagenic etheno derivatives. We hypothesized that a functionally similar and potentially mutagenic compound, that is, 13-oxo-9,10-epoxytridecenoic acid (OETA), would be generated from 9-HPODE through an analogous fragmentation. We expected that an ester of 2-lysophosphatidylcoline (PC), OETA-PC, would be produced by oxidative cleavage of 9-HPODE-PC in biological membranes. An efficient, unambiguous total synthesis of trans-OETA-PC was first executed to provide a standard that could facilitate the identification of this phospholipid epoxyalkenal that was shown to be produced during oxidation of the linoleic acid ester of 2-lysoPC. Finally, trans-OETA-PC was detected in a lipid extract from rat retina. The identity of the naturally occurring oxidatively truncated phospholipid was further confirmed by derivatization with methoxylamine that produced characteristic mono and bis adducts. The average amount of trans-OETA-PC in rat retina, 0.33 pmol, is relatively low as compared to other oxidatively truncated PCs, for example, the 4-hydroxy-7-oxohept-5-enoic acid PC ester (2.5 pmol) or the 4-keto-7-oxohept-5-enoic acid PC ester (1.7 pmol), derived from the docosahexaenoic acid ester of 2-lysoPC. This, most likely, is because docosahexaenoate PCs are particularly abundant in the retina as compared to the linoleate PC ester precursor of OETA-PC. As predicted by analogy with 4,5-EDE, OETA-PC reacts with dAdo and dGuo, as well as with DNA, to form mutagenic etheno adducts.
先前，我们通过与多不饱和脂肪酸氧化断裂产生的非磷脂产物进行类比，发现了多种具有生物活性的氧化截断磷脂。此前，人们发现 4,5-环氧-2(E)-癸烯醛（4,5-EDE）是由 13-(S)-过氧-9,11-(Z,E)-十八碳二烯酸（13-HPODE）氧化断裂产生的。4,5-EDE 与脱氧腺苷（dAdo）和脱氧鸟苷（dGuo）反应，形成致突变的乙撑衍生物。我们假设一种功能相似且具有潜在致突变性的化合物，即 13-氧代-9,10-环氧十三碳烯酸（OETA），将通过类似的断裂从 9-HPODE 生成。我们预计，生物膜中 9-HPODE-PC 的氧化断裂将产生 2-溶血磷脂酰胆碱（PC）的酯，即 OETA-PC。我们首先成功地进行了反式-OETA-PC 的高效、明确的全合成，为鉴定这种磷脂环氧丙烯醛提供了标准，该化合物在亚油酸酯 2-溶血 PC 的氧化过程中被证明产生。最后，在大鼠视网膜的脂质提取物中检测到反式-OETA-PC。用甲氧基胺衍生化进一步证实了天然存在的氧化截断磷脂的身份，产生了特征性的单加合物和双加合物。与其他氧化截断的 PCs 相比，大鼠视网膜中反式-OETA-PC 的平均含量相对较低，例如，来源于 2-溶血 PC 二十二碳六烯酸酯的 4-羟基-7-氧庚-5-烯酸 PC 酯（2.5 pmol）或 4-酮-7-氧庚-5-烯酸 PC 酯（1.7 pmol）。这很可能是因为与 OETA-PC 的前体亚油酸酯相比，二十二碳六烯酸酯 2-溶血 PC 特别丰富。与 4,5-EDE 类比预测，OETA-PC 与 dAdo 和 dGuo 以及 DNA 反应，形成致突变的乙撑加合物。
