致癌性多环芳胺诱导形成DNA加合物的新机制:自由基或氮正离子
详细信息 查看官网全文
- 英文论文题名：Mechanism for DNA Adduct Formation induced by the Carcinogenic Polyaromatic Amines:Free Radical or Nitrenium Pathway?
- 论文作者：黄春华 ; 朱本占
- 英文论文作者：Chun-Hua Huang ; Ben-Zhan Zhu ; State Key Laboratory of Environmental Chemistry and Ecotoxicology ; Research Center for Eco-Environmental Sciences ; Chinese Academy of Sciences
- 年：2016
- 作者机构：中国科学院生态环境研究中心环境化学与生态毒理学国家重点实验室;
- 论文关键词：异羟肟酸 ; 碳自由基 ; 芴 ; DNA ; 自由基重排
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十六分会：环境化学
- 语种：中文
- 分类号：R114
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十六分会 ; 环境化学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：181k
- 原文格式：D
- 会议级别：全国
摘要
具遗传毒性的氨基芴(AF)已经被广泛用作于实验中的模型致癌物质。先前的研究提出氨基芴的致癌机理可能是通过酶的作用生成N-羟基-乙酰基氨基芴(N-OH-AAF)中间产物,其在磺酸转移酶的作用下可能会产生反应活性很强的氮正离子中间体;该氮正离子会直接进攻DNA,形成两种DNA加合物。本研究发现卤代苯醌与N-OH-AAF的化学反应与酶促反应有明显的不同:1)卤代苯醌在不需要酶催化的条件下就可以促使N-OH-AAF与d G形成DNA加合物;2)在该体系中检测到了四种不同结构的DNA加合物,其中两种是先前未曾发现的新型DNA加合物。有趣的是,我们不仅在卤代苯醌/N-OH-AAF体系中检测到了新型的以芴环碳为中心的自由基,更重要的是,在经典的N-OH-AAF硫酸酯体系中也检测到了这个自由基。这些结果表明致癌中间产物N-OH-AAF可能会通过自由基,而非先前提出氮正离子途径,与DNA形成加合物。基于以上数据,我们提出了卤代苯醌与N-OH-AAF诱导产生d G加合物的新型反应机理:N-OH-AAF通过亲核进攻卤代苯醌,形成醌中间体,其很不稳定,会均裂生成以氧为中心的醌自由基和以氮为中心的N-AAF自由基,其会通过共振互变形成三种不同的以芴环碳为中心的自由基。这四种自由基都会进攻d G形成四种不同的加合物。本研究首次提出了N-OH-AAF与DNA形成加合物可能是通过新型的自由基反应机理进行并首次检测到两种新型DNA加合物,对进一步深入研究多环芳胺的致癌机理具有重要的理论意义。
The genotoxic agent 2-aminofluorene(AF) has been widely used as a model carcinogen in experimental studies.It has been reported that 2-aminofluorene could be metabolically activated to N-hydroxy-2-acetylaminofluorene(N-OH-AAF) in vivo,probably resulting in the formation of reactive nitrenium ions,which could attack DNA to form two DNA adducts.Compared enzymatic reaction,we observed significant differences in the chemical reaction between XBQs and N-OH-AAF:1) XBQs could induce DNA adduct formation between N-OH-AAF and DNA non-enzymatically.2) Four different DNA adducts were observed,two of which have never been reported before.A new carbon-centered radical was observed not only in XBQs/N-OH-AAF,but more importantly,also during decomposition of N-OH-AAF sulfate ester.These results suggest that the carcinogenesis of N-OH-AAF may occur through a radical pathway.Based on these data,a unique mechanism for DNA adduct formation by XBQs/N-OH-AAF was proposed:A nucleophilic reaction may take place between XBQs and N-OH-AAF,forming a quinone intermediate,which can decompose homolytically to produce the oxygen-centered quinone enoxy radical,and nitrogen-centered radical ·N-AAF,which could isomerize to form three different kinds of carbon-centered radicals on fluorene ring.The four radical isomers may attack d G on DNA,then produce four different DNA adducts.This study represents the first report that the DNA adducts might be induced by N-OH-AAF via a new radical mechanism,which may have great theoretical importance for further studies on the carcinogenic mechanism of the polyaromatic amines.
The genotoxic agent 2-aminofluorene(AF) has been widely used as a model carcinogen in experimental studies.It has been reported that 2-aminofluorene could be metabolically activated to N-hydroxy-2-acetylaminofluorene(N-OH-AAF) in vivo,probably resulting in the formation of reactive nitrenium ions,which could attack DNA to form two DNA adducts.Compared enzymatic reaction,we observed significant differences in the chemical reaction between XBQs and N-OH-AAF:1) XBQs could induce DNA adduct formation between N-OH-AAF and DNA non-enzymatically.2) Four different DNA adducts were observed,two of which have never been reported before.A new carbon-centered radical was observed not only in XBQs/N-OH-AAF,but more importantly,also during decomposition of N-OH-AAF sulfate ester.These results suggest that the carcinogenesis of N-OH-AAF may occur through a radical pathway.Based on these data,a unique mechanism for DNA adduct formation by XBQs/N-OH-AAF was proposed:A nucleophilic reaction may take place between XBQs and N-OH-AAF,forming a quinone intermediate,which can decompose homolytically to produce the oxygen-centered quinone enoxy radical,and nitrogen-centered radical ·N-AAF,which could isomerize to form three different kinds of carbon-centered radicals on fluorene ring.The four radical isomers may attack d G on DNA,then produce four different DNA adducts.This study represents the first report that the DNA adducts might be induced by N-OH-AAF via a new radical mechanism,which may have great theoretical importance for further studies on the carcinogenic mechanism of the polyaromatic amines.
引文