Schneider Claus, Boeglin William E, Yin Huiyong, Ste Donald F, Hachey David L, Porter Ned A, Brash Alan R
Department of Pharmacology, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
Lipids. 2005 Nov;40(11):1155-62. doi: 10.1007/s11745-005-1480-3.
The cytotoxic aldehydes 4-hydroxynonenal, 4-hydroperoxynonenal (4-HPNE), and 4-oxononenal are formed during lipid peroxidation via oxidative transformation of the hydroxy or hydroperoxy precursor fatty acids, respectively. The mechanism of the carbon chain cleavage reaction leading to the aldehyde fragments is not known, but Hock-cleavage of a suitable dihydroperoxide derivative was implicated to account for the fragmentation [Schneider, C., Tallman, K.A., Porter, N.A., and Brash, A.R. (2001) Two Distinct Pathways of Formation of 4-Hydroxynonenal. Mechanisms of Nonenzymatic Transformation of the 9- and 13-Hydroperoxides of Linoleic Acid to 4-Hydroxyalkenals, J. Biol. Chem. 275, 20831-20838]. Both 8,13- and 10,13-dihydroperoxyoctadecadienoic acids (diHPODE) could serve as precursors in a Hock-cleavage leading to 4-HPNE via two different pathways. Here, we synthesized diastereomeric 9,12-, 10,12-, and 10,13-diHPODE using singlet oxidation of linoleic acid. 8,13-Dihydroperoxyoctadecatrienoic acid was synthesized by vitamin E-controlled autoxidation of gamma-linolenic acid followed by reaction with soybean lipoxygenase. The transformation of these potential precursors to 4-HPNE was studied under conditions of autoxidation, hematin-, and acid-catalysis. In contrast to 9- or 13-HPODE, neither of the dihydroperoxides formed 4-HPNE on autoxidation (lipid film, 37 degrees C), regardless of whether the free acid or the methyl ester derivative was used. Acid treatment of 10,13-diHPODE led to the expected formation of 4-HPNE as a significant product, in accord with a Hock-type cleavage reaction. We conclude that, although the suppression of 4-H(P)NE formation from monohydroperoxides by alpha-tocopherol indicates peroxyl radical reactions in the major route of carbon chain cleavage, the dihydroperoxides previously implicated are not intermediates in the autoxidative transformation of monohydroperoxy fatty acids to 4-HPNE and related aldehydes.
细胞毒性醛类物质4-羟基壬烯醛、4-氢过氧壬烯醛（4-HPNE）和4-氧代壬烯醛分别在脂质过氧化过程中通过羟基或氢过氧前体脂肪酸的氧化转化形成。导致醛片段的碳链裂解反应机制尚不清楚，但一种合适的二氢过氧化物衍生物的霍克裂解被认为可以解释这种碎片化过程[施奈德，C.，塔尔曼，K.A.，波特，N.A.，和布拉什，A.R.（2001年）4-羟基壬烯醛形成的两种不同途径。亚油酸的9-和13-氢过氧化物非酶转化为4-羟基烯醛的机制，《生物化学杂志》275，20831 - 20838]。8,13-和10,13-二氢过氧化十八碳二烯酸（二氢过氧化二烯酸）都可以通过两种不同途径作为霍克裂解中导致4-HPNE的前体。在这里，我们利用亚油酸的单线态氧化合成了非对映体的9,12-、10,12-和10,13-二氢过氧化二烯酸。8,13-二氢过氧化十八碳三烯酸是通过γ-亚麻酸的维生素E控制的自氧化反应，然后与大豆脂氧合酶反应合成的。在自氧化、血红素和酸催化条件下研究了这些潜在前体向4-HPNE的转化。与9-或13-氢过氧二烯酸不同，无论使用游离酸还是甲酯衍生物，在自氧化（脂质膜，37℃）条件下，这两种二氢过氧化物都不会形成4-HPNE。对10,13-二氢过氧化二烯酸进行酸处理会导致预期的4-HPNE作为主要产物形成，这与霍克型裂解反应一致。我们得出结论，尽管α-生育酚抑制单氢过氧化物形成4-H（P）NE表明在碳链裂解的主要途径中存在过氧自由基反应，但之前涉及的二氢过氧化物不是单氢过氧脂肪酸自氧化转化为4-HPNE及相关醛类的中间体。
