Study of Oxidative damages on guanine adducts and hunting of markers for damages on DNA by means of electrochemical methods

近年来的医学统计研究表明，乙醛（AA）对DNA的损伤是饮酒致癌的始动作用之一。环丙鸟嘌呤（CPrG）是AA损伤DNA的最有希望的候选者。基于氧化损伤过程中电子沿沿着DNA链通过π-π堆积的理论，我研究了在DNA上形成CPrG后的额外氧化，作为AA形成CPrG所发生的DNA碱基序列误读机制的一部分。CPrG在水介质中的电解氧化产生了独特的二聚体化合物CPrG作为主要产物。详细的NMR研究表明，每个CPrG部分具有非常相似但不相同的结构，表示化学位移彼此略有不同。此外，每个CPrG部分上的连接位点决定在CPrG上的某些不同位置。二聚体的预期结构得到了MS/MS数据的有力支持。所鉴定的结构可以通过CPrG本身与通过消除两个电子和一个质子产生的CPrG的碳正离子之间的偶联形成。该反应路线得到了分子轨道计算的支持。MOPAC构象研究表明，二聚体可以形成一个intrastrand mannar和interstrand的方式在DNA中，特别是，前者的方式可以归因于DNA信息的误读。包括CPrG，并在处理过的DNA中发现了二聚体结构。二聚体可能成为一个有价值的生物标志物，指示饮酒者致癌风险的大小。

Some recent statistical studies in medicine suggest that DNA damages by acetaldehyde (AA) is one of initial actions in carcinogenesis occurred by drinking. Cyclic-propanoguanine (CPrG) will be the most expected candidate as a damaged form in DNA by AA. Based on the theory of electron-hopping along DNA chains through π-π stacking in an oxidative damaging process, I have investigated additional oxidations following the formation of CPrG on DNA as a part of a mis-reading mechanism of base sequences in DNA occurred by CPrG formation by AA.Electrolytic oxidation of CPrG in aqueous media generated a unique dimer compound of CPrG as a major product. Detailed NMR studies indicated that the each CPrG parts had very similar but not same structure representing chemical shifts different a little from each other. Additionally, the linkage sites on each CPrG moieties decided to be certain different positions on CPrG. The expected structure of the dimer has been strongly supported by MS/MS data.The identified structure can be formed by coupling between CPrG itself and a carbocation of CPrG that will be generated via elimination of both two electrons and a proton. This proposed reaction route has been supported by a MO calculation. Conformational studies with MOPAC suggest that the dimer can be formed with an intrastrand mannar and an interstrand manner in DNA and, particularly, the former manner can be attributable to the mis-reading of DNA information.Quite recently I have performed electrolysis of treated DNA double strands (Calf thymus). including CPrG and have found the dimer structure in the treated DNA. The dimer may become an valuable biomarker indicating magnitude of risk of carcinogenesis for drinkers.