Cadet Jean, Ravanat Jean-Luc, Martinez Glaucia R, Medeiros Marisa H G, Di Mascio Paolo
Laboratoire Lésions des Acides Nucléiques, DRFMC/SCIB-UMR-E No. 3 (CEA/UJF), CEA/Grenoble, F-38054 Grenoble Cedex 9, France.
Photochem Photobiol. 2006 Sep-Oct;82(5):1219-25. doi: 10.1562/2006-06-09-IR-914.
This survey focuses on recent aspects of the singlet oxygen oxidation of the guanine moiety of nucleosides, oligonucleotides, isolated and cellular DNA that has been shown to be the exclusive DNA target for this biologically relevant photogenerated oxidant. A large body of mechanistic data is now available from studies performed on nucleosides in both aprotic solvents and aqueous solutions. A common process to both reaction conditions is the formation of 8-oxo-7,8-dihydroguanine by reduction of 8-hydroperoxyguanine that arises from the rearrangement of initially formed endoperoxide across the 4,8-bond of the purine moiety. However, in organic solvent the hydroperoxide is converted as a major degradation pathway into a dioxirane that subsequently decomposes into a complex pattern of oxidation products. A different reaction that involved the formation of a highly reactive quinonoid intermediate consecutively to the loss of a water molecule from the 8-hydroperoxide has been shown to occur in aqueous solution. Subsequent addition of a water molecule at C5 leads to the generation of a spiroiminodihy-dantoin compound via a rearrangement that involves an acyl shift. However, in both isolated and cellular DNA the latter decomposition pathway is at the best a minor process, because only 8-oxo-7,8-dihydroguanine has been found to be generated. It is interesting to point out that singlet oxygen has been shown to contribute predominantly to the formation of 8-oxo-7,8-dihydroguanine in the DNA of bacterial and human cells upon exposure to UVA radiation. It may be added that the formation of secondary singlet-oxygen oxidation products of 8-oxo-7,8-dihydroguanine, including spiroiminodihydantoin and oxaluric acid that were characterized in nucleosides and oligonucleotide, respectively, have not yet been found in cellular DNA.
本综述聚焦于核苷、寡核苷酸、分离的DNA和细胞DNA中鸟嘌呤部分的单线态氧氧化的最新研究进展，单线态氧已被证明是这种具有生物学相关性的光生氧化剂唯一的DNA作用靶点。目前，在非质子溶剂和水溶液中对核苷进行的大量研究已获得了丰富的机理数据。两种反应条件下的一个共同过程是，通过还原8-氢过氧鸟嘌呤生成8-氧代-7,8-二氢鸟嘌呤，8-氢过氧鸟嘌呤由最初形成的内过氧化物跨嘌呤部分的4,8-键重排产生。然而，在有机溶剂中，氢过氧化物作为主要降解途径会转化为二环氧乙烷，随后分解为复杂的氧化产物模式。在水溶液中已证明发生了一种不同的反应，该反应涉及在8-氢过氧化物失去一个水分子后形成高反应性的醌型中间体。随后在C5处添加一个水分子，通过涉及酰基迁移的重排反应生成螺亚胺二氢尿嘧啶化合物。然而，在分离的DNA和细胞DNA中，后一种分解途径充其量只是一个次要过程，因为仅发现生成了8-氧代-7,8-二氢鸟嘌呤。值得指出的是，已证明单线态氧在细菌和人类细胞的DNA暴露于UVA辐射时，对8-氧代-7,8-二氢鸟嘌呤的形成起主要作用。还可以补充的是，在细胞DNA中尚未发现8-氧代-7,8-二氢鸟嘌呤的次级单线态氧氧化产物的形成，包括分别在核苷和寡核苷酸中鉴定出的螺亚胺二氢尿嘧啶和草尿酸。
