Barlow T, Takeshita J, Dipple A
Chemistry of Carcinogenesis Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, P.O. Box B, Frederick, Maryland 21702, USA.
Chem Res Toxicol. 1998 Jul;11(7):838-45. doi: 10.1021/tx980038d.
In reactions between styrene oxide and the ring nitrogen at the 1-position of deoxyadenosine, the epoxide is opened at both the alpha- (benzylic) and beta-carbons. The 1-substituted nucleosides formed are unstable and subsequently undergo either Dimroth rearrangement to give N6-substituted deoxyadenosines or deamination to give 1-substituted deoxyinosines. alphaN6-Substituted compounds are also formed from direct reaction at the exocyclic nitrogen. Kinetic experiments revealed that relative rates of deamination of 1-substituted deoxyadenosine-styrene oxides and 1-substituted adenosine-styrene oxides were similar. However, the rate of Dimroth rearrangement in beta1-substituted adenosine-styrene oxides was approximately 2.3-fold greater than that of beta1-substituted deoxyadenosine-styrene oxides and approximately 1.5-fold greater in alpha1-substituted adenosine-styrene oxides relative to alpha1-substituted deoxyadenosine-styrene oxides. Analysis of the products formed from reactions of styrene oxide with [3H]deoxyadenosine and [3H]deoxyadenosine incorporated into native and denatured DNA showed that the double-helical DNA structure reduced the levels of adducts formed 5-fold relative to denatured DNA but did not present a complete barrier to formation of either N6-substituted deoxyadenosine- or 1-substituted deoxyinosine-styrene oxide adducts in native DNA. Additionally, in denatured and native DNA the product distributions were altered in favor of formation of beta1-substituted deoxyinosine-styrene oxide adducts with respect to reactions of the nucleoside. The ratio of retained to inverted configuration of alphaN6-substituted products was higher in DNA than in nucleoside reactions. These experiments indicate that in addition to the N6-position, the ring nitrogen at the 1-position of deoxyadenosine is available, to some extent, for reaction in native DNA. In styrene oxide-DNA reactions, formation of 1-substituted adenines can lead to deaminated products where both Watson-Crick hydrogen-bonding sites are disrupted.
在氧化苯乙烯与脱氧腺苷1位上的环氮之间的反应中，环氧化物在α-（苄基）和β-碳处均发生开环。形成的1-取代核苷不稳定，随后要么发生迪莫思重排生成N6-取代的脱氧腺苷，要么发生脱氨基反应生成1-取代的脱氧肌苷。αN6-取代的化合物也可由环外氮的直接反应形成。动力学实验表明，1-取代的脱氧腺苷-氧化苯乙烯和1-取代的腺苷-氧化苯乙烯的脱氨基相对速率相似。然而，β1-取代的腺苷-氧化苯乙烯中的迪莫思重排速率比β1-取代的脱氧腺苷-氧化苯乙烯快约2.3倍，相对于α1-取代的脱氧腺苷-氧化苯乙烯，α1-取代的腺苷-氧化苯乙烯中的迪莫思重排速率快约1.5倍。对氧化苯乙烯与[3H]脱氧腺苷以及掺入天然和变性DNA中的[3H]脱氧腺苷反应生成的产物分析表明，双螺旋DNA结构使形成的加合物水平相对于变性DNA降低了5倍，但对于天然DNA中N6-取代的脱氧腺苷-或1-取代的脱氧肌苷-氧化苯乙烯加合物的形成并非完全阻碍。此外，在变性和天然DNA中，产物分布发生改变，有利于相对于核苷反应形成β1-取代的脱氧肌苷-氧化苯乙烯加合物。DNA中αN6-取代产物的保留构型与转化构型之比高于核苷反应中的该比值。这些实验表明，除了N6位之外，脱氧腺苷1位上的环氮在一定程度上也可用于天然DNA中的反应。在氧化苯乙烯-DNA反应中，1-取代腺嘌呤的形成可导致脱氨基产物，其中沃森-克里克氢键结合位点均被破坏。
