致癌性卤代醌与有机氢过氧化物不依赖金属分解的分子机制及其潜在生物学意义  

Metal-independent decomposition of organic hydroperoxides by the halogenated quinoid carcinogens and the potential biological implications

作　　者：朱本占 刘玉祥[1,2] 任福荣[1,2] 黄春华 

机构地区：[1]环境化学与生态毒理学国家重点实验室 [2]中国科学院生态环境研究中心,北京100085

出　　处：《中国科学：化学》2015年第7期692-702,共11页SCIENTIA SINICA Chimica

基　　金：中国科学院战略性先导科技专项(B类)(XDB01020300);国家自然科学基金(21237005;21321004;20925724;21407163);中国博士后科学基金(2014M561078))资助

摘　　要：卤代醌是一类具有致癌活性的化合物.最近,它们作为氯代消毒副产物在饮用水中被检测到.有机氢过氧化物(ROOH)可通过自由基和酶促反应氧化多不饱和脂肪酸产生.先前的研究表明,ROOH可被过渡金属催化分解产生烷氧自由基,从而启动脂质过氧化或进一步分解生成α,β-不饱和醛.然而,目前还不清楚卤代醌能否不依赖过渡金属离子与ROOH以类似方式生成烷氧自由基.综合采用电子自旋共振-自旋捕获、高分辨液相色谱质谱联用及其他分析方法,结果发现,2,5-二氯-1,4-苯醌(DCBQ)可显著增强典型的有机氢过氧化物叔丁基过氧化氢(t-BuO OH)分解,以不依赖金属离子的方式生成叔丁氧自由基.在以上发现的基础上,我们检测和鉴定出一类新型的以碳为中心的醌酮自由基,其是我们之前推测的以氧为中心的醌氧自由基的自旋异构体.我们进而将研究扩展到更具生理意义的内源性脂质氢过氧化物13-过氧羟基-9,11-十八碳二烯酸(13-HPODE)中,发现DCBQ也可以显著增加13-HPODE的分解,产生脂质烷基自由基和具有基因毒性的4-羟基-2-壬烯醛.其他卤代醌也具有类似作用.研究表明,致癌性卤代醌能通过一类新型的不依赖于金属离子的亲核取代和均裂分解的机制,促进有机氢过氧化物分解并生成具有较强反应活性的烷氧、醌酮和脂质烷基自由基,及具有基因毒性的4-羟基-2-壬烯醛.以上研究结果可部分解释卤代醌及其酚类前驱物为何具有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. Organic hydroperoxides（ROOH） can be produced both by free radical reactions and enzymatic oxidation of polyunsaturated fatty acids. ROOH have been shown to undergo transition metal-catalyzed decomposition to alkoxyl radicals, which may initiate lipid peroxidation or further decompose to the reactive a, β-unsaturated aldehydes. However, it is not clear whether halogenated quinones react in a similar fashion with ROOH to produce alkoxyl radicals independent of transition metals. By complementary applications of ESR spin-trapping, HPLC/high resolution mass spectrometric and other analytical methods, we found that 2,5-dichloro-1,4-benzoquinone（DCBQ） could markedly enhance the decomposition of a model ROOH tert-butylhydroperoxide,leading to the formation of t-butoxyl radicals independent of transition metals. Based on the above findings, we detected and identified, for the first time, an unprecedented carbon-centered quinone ketoxy radical, which is the spin isomer of the proposed oxygen-centered quinone enoxy radical. Then we extended our study to the more physiologically relevant endogenous lipid hydroperoxide 13-hydroperoxy-9,11-octadecadienoic acid, and found that DCBQ could also markedly enhance its decomposition to produce the reactive lipid alkyl radicals and the genotoxic 4-hydroxy-2-nonenal（HNE）. Analogous results were observed with other halogenated quinones. In summary, these findings demonstrated that halogenated quinoid carcinogens can enhance the decomposition of ROOH and formation of reactive alkoxyl, quinone ketoxy, lipid alkyl radicals and genotoxic HNE via a novel metal-independent nucleophilic substitution coupled with homolytic decomposition mechanism, which may partly explain their potential genotoxicity and carcinogenicity.

关 键 词：有机氢过氧化物 电子共振-自旋捕获 烷氧自由基 醌酮自由基 4-羟基-2-壬烯醛 

分 类 号：O621.13[理学—有机化学]