1,3-丁二烯与DNA交联机理的研究——代谢产物在DNA大沟股间交联反应的AM1计算

采用ＡＭ１方法计算了环境致癌物１，３－丁二烯（ＢＤ）的代谢产物１，２－环氧－３，４－丁烯（ＥＢ）和１，２，３，４－二环氧丁烷（ＤＥＢ）与ＤＮＡ腺嘌呤和胞嘧啶烷化反应过程速率控制步骤的活化能，以及ＤＥＢ在ＤＮＡ大沟侧与不同序列ＤＮＡ片断生成烷化股间横向交联产物的结构和能量．结论认为：用烷化反应的难易程度难以解释ＤＥＢ的致突性比ＥＢ约大１００倍的实验事实；强致突的ＤＥＢ可与碱基发生２次烷化反应，生成ＤＮＡ交联产物；而ＥＢ则不能交联，这可能为２者基因毒性差异巨大的分子机制；同时ＤＥＢ在ＤＮＡ大沟侧可与多种不同的ＤＮＡ序列发生股间横向交联，对比在小沟侧只与２种序列交联，此发生股间横交联几率的差异合理地解释了ＤＥＢ致突的碱基选择性

Studies on Carcinogenic Mechanism of 1,3-ButadieneComputating Metabolites of 1,3-Butadiene Interstrand Crosslinking with DNA by AM1

The alkylating reaction of 1,2Epoxy3,4Butene(EB)and 1,2,3,4DiEpoxyButane(DEB),the metabolites of rodent carcinogenic 1,3Butadiene,with Adenine and Cytosine and interaction with fragment of DNA have been computedThe results show that it is difficult to explain the fact that the mutagenicity of DEB is 100 times greater than that of EB by the ability of alkylation,and also show that DEB can interstrand crosslink with DNA through two times alkylating reactions,but EB cannotSo,this difference may contribute to the significant different carcinogenicity of two agentsMeanwhile,it is known that DEB can interstrand crosslink with many sequences of DNA in major groove vstwo in minor grooveThis increases opportunities of interstrand crosslink with DNAThis difference may be the reason of base selection of DEB mutationThe deformation of some crosslinked DNA may also contribute to this selection in some degree