Guanine-adenine DNA cross-linking by 1,2,3,4-diepoxybutane: potential basis for biological activity.
Guanine-adenine DNA cross-linking by 1,2,3,4-diepoxybutane: potential basis for biological activity.
复制标题
1,2,3,4-二环氧丁烷的鸟嘌呤-腺嘌呤 DNA 交联：生物活性的潜在基础。
DOI：
10.1021/tx0498206
复制
发表时间：
2004
影响因子：
4.1
通讯作者：
Tretyakova,Natalia
中科院分区：
文献类型：
--
作者：
Park,Soobong;Hodge,Jacob;Anderson,Christopher;Tretyakova,Natalia
1，2，3，4-二氧基丁烷(DEB)是1，3-丁二烯(1，3-BD)的主要致癌代谢产物，1，3-丁二烯是一种重要的工业化学品，也是一种存在于卷烟和汽车尾气中的环境污染物。DEB能够诱导多种遗传毒性效应，包括点突变、大片段缺失和染色体异常。DEB的致突变性和致癌性被认为是由于它能够通过使−双螺旋内的两个核苷酸碱基相继烷基化而形成双功能DNADNA加合物。我们最近报道了DEB诱导的DNA−DNA交联会导致1，4-二(关基-7-基)-2，3-丁二醇(bi-N7G-BD)加合物的形成[Park，S.，and Tretyakova，N.(2004年)1，2，3，4-二环氧基丁烷的主要DNA-−-DNA交联物的结构特征]。Toxicol资源。17(2)、129−136]。然而，二苯基乙二胺引起的鸟嘌呤−交联不能解释暴露于二乙基二乙胺和1，3-BD后A：T碱基对突变的发生。在本工作中，在外消旋−处理的双链DNADNA中发现了四个涉及腺嘌呤和鸟嘌呤核苷酸碱基的不对称DNADNADNA交联链。1-(亚丁-1-基)-4-(冠-7-基)-2，3-丁二醇(N1A-N7G-BD)，1-(亚丁-3-基)-4-(冠-7-基)-2，3-丁二醇(N3A-N7G-BD)，1-(亚丁-7-基)-4-(冠-7-基)-2，3-丁二醇(N7A-N7G-BD)，和1-(亚丁-N-6-基)-4-(冠-7-基)-2，3-丁二醇(N6A-N7G-BD)。尽管在双链−中鸟嘌呤DNA腺嘌呤损伤的丰度比相应的双N7G交联物少10倍，但N1A-N7G-BD和N6A-N7G-BD在水解性方面更稳定，如果在体内形成，可能会在靶组织中积聚。对合成−双链5‘-(GGT)5、5’-(GT)7G和5‘-(GAA)5(+-链)诱导的鸟嘌呤-腺嘌呤-DEB交联物的高效液相-电喷雾-质谱学分析表明，G-−A主要产生1，3-链间N1a-N7G损伤。双功能鸟嘌呤−腺嘌呤加合物的形成可能有助于在暴露于DEB后AT碱基对替换和缺失突变。
1,2,3,4-Diepoxybutane (DEB) is a prominent carcinogenic metabolite of 1,3-butadiene (1,3-BD), an important industrial chemical and an environmental pollutant found in cigarette smoke and automobile exhaust. DEB is capable of inducing a variety of genotoxic effects, including point mutations, large deletions, and chromosomal aberrations. The mutagenicity and carcinogenicity of DEB are thought to result from its ability to form bifunctional DNA−DNA adducts by sequentially alkylating two nucleobases within the DNA double helix. We recently reported that DEB-induced DNA−DNA cross-linking leads to the formation of 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) adducts [Park, S., and Tretyakova, N. (2004) Structural characterization of the major DNA−DNA cross-link of 1,2,3,4-diepoxybutane.Chem. Res. Toxicol. 17(2), 129−136]. However, guanine−guanine cross-linking by DEB cannot explain the development of A:T base pair mutations following exposure to DEB and 1,3-BD. In the present work, four asymmetrical DNA−DNA cross-links involving both adenine and guanine nucleobases were identified in double-stranded DNA treated with racemic DEB. These novel lesions were assigned the structures of 1-(aden-1-yl)-4-(guan-7-yl)-2,3-butanediol (N1A-N7G-BD), 1-(aden-3-yl)-4-(guan-7-yl)-2,3-butanediol (N3A-N7G-BD), 1-(aden-7-yl)-4-(guan-7-yl)-2,3-butanediol (N7A-N7G-BD), and 1-(aden-N6-yl)-4-(guan-7-yl)-2,3-butanediol (N6A-N7G-BD), based on the comparison of their MS/MS spectra, HPLC retention times, and UV spectra with those of the corresponding authentic standards prepared independently. Although guanine−adenine lesions are ∼10 times less abundant in DEB-treated double-stranded DNA than the corresponding bis-N7G cross-links, N1A-N7G-BD and N6A-N7G-BD are more hydrolytically stable and, if formed in vivo, may accumulate in target tissues. HPLC-ESI-MS/MS analysis of guanine−adenine DEB cross-links induced in synthetic DNA duplexes 5‘-(GGT)5, 5‘-(GT)7G, and 5‘-(GAA)5(+-strand) demonstrate that G−A cross-linking by DEB produces primarily 1,3-interstrand N1A-N7G lesions. The formation of bifunctional guanine−adenine adducts is likely to contribute to AT base pair substitutions and deletion mutations following DEB exposure.