致癌性卤代醌介导的脂质氢过氧化物分解的分子机制

Molecular mechanism of metal-independent decomposition of lipid hydroperoxide by the carcinogenic halogenated quinones

卤代醌是许多卤芳香持久有机污染物的致癌代谢产物和饮用水消毒副产物.13-过氧羟基-9,11-十八碳二烯酸(13-HPODE)是最为广泛研究的内源性脂质过氧化物.众所周知,过渡金属离子可以催化分解13-HPODE,但尚不清楚卤代醌是否可以通过不依赖金属离子的途径促进其分解;若是如此,又有什么特异性和相似性?我们发现卤化醌如2,5-二氯-1,4-苯醌(DCBQ)可显著促进13-HPODE的分解.综合采用电子自旋共振-自旋捕获、HPLC-MS和GC-MS等分析方法,可检测到反应形成的脂质烷基自由基如戊烷基自由基、7-羧甲基自由基以及具有基因毒性的4-羟基-2-壬烯醛(HNE)等.在DCBQ和13-HPODE的反应中也能检测到两种氯醌-脂质烷氧基耦合物.我们认为卤代醌促进内源性脂质过氧化物13-HPODE分解生成活性脂质烷基自由基和基因毒性的HNE是通过一类新型的金属非依赖亲核取代与裂解机理来实现的,这也在一定程度上解释了其潜在的基因毒性和致癌性.

Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. 13-Hydroperoxy-9,11-octadecadienoic acid（ 13-HPODE） is the most extensively studied endogenous lipid hydroperoxide. Although it is well known that the decomposition of 13-HPODE can be catalyzed by transition metal ions,it is not clear whether halogenated quinones could enhance its decomposition independent of metal ions,and if so,what are the unique characteristics and similarities？ We found that halogenated quinones such as2,5-dichloro-1,4-benzoquinone（ DCBQ） could markedly enhance the decomposition of 13-HPODE and formation of the reactive lipid alkyl radicals such as pentyl and 7-carboxyheptyl radicals,and the genotoxic 4-hydroxy-2-nonenal（ HNE）, through the complementary application of ESR spintrapping,HPLC-MS and GC-MS methods. Interestingly,two chloroquinone-lipid alkoxyl conjugates were also detected and identified from the reaction between DCBQ and 13-HPODE. We propose that the enhanced decomposition of the endogenous lipid hydroperoxide 13-HPODE by halogenatedquinones and formation of reactive lipid alkyl radicals and genotoxic HNE is through a novel metalindependent nucelophilic substitution coupled with homolytic decomposition mechanism,which may partly explain their potential genotoxicity and carcinogenicity.