Radiation-induced formation of purine 5′,8-cyclonucleosides in isolated and cellular DNA: high stereospecificity and modulating effect of oxygen
Radiation-induced formation of purine 5′,8-cyclonucleosides in isolated and cellular DNA: high stereospecificity and modulating effect of oxygen
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DOI：
10.1039/c004531d
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发表时间：
2010-01-01
影响因子：
3.2
通讯作者：
Cadet, Jean
中科院分区：
文献类型：
--
作者：
Belmadoui, Nourreddine;Boussicault, Fabien;Cadet, Jean
本工作旨在获得结论性的机理的见解辐射诱导形成的腺嘌呤和鸟嘌呤5 '，8-环-2'-脱氧核糖核苷的5 'R和5'S非对映异构体，重点是描绘的O-2在分离和细胞DNA的抑制作用。通过HPLC-MS/MS评估的嘌呤5 '，8-环-2'-脱氧核糖核苷的水平被发现随着O-2浓度的增加而稳定地降低，对于低O-2浓度，5 '，8-环-2'-脱氧鸟苷比5 '，8-环-2'-脱氧腺苷更有效地产生。在C5 '-C8键的产生和随后的氧化步骤之后，在嘌呤的C8上的C5'自由基的分子内加成中观察到高立体选择性，从而导致对于两种嘌呤5 '，8-环己基糖苷的5' R非对映体的主要形成。在O-2存在下4个串联损伤的形成产率降低至少部分地解释了细胞DNA中嘌呤5 '，8-环-2'-脱氧核糖核苷的辐射诱导产率的低效率，其比先前报道的从HPLC-MS分析获得的数据低约两个数量级。
The present work is aimed at gaining conclusive mechanistic insights into the radiation-induced formation of the 5'R and 5'S diastereomers of both adenine and guanine 5',8-cyclo-2'-deoxyribonucleosides, with emphasis on the delineation of the inhibitory effect of O-2 in isolated and cellular DNA. The levels of purine 5',8-cyclo-2'-deoxyribonucleosides as assessed by HPLC-MS/MS were found to decrease steadily with the increase of O-2 concentration,the 5',8-cyclo-2'-deoxyguanosine being produced more efficiently than the 5',8-cyclo-2'-deoxyadenosine for low O-2 concentrations. A high stereoselectivity was observed in the intramolecular addition of the C5' radical to the C8 of the purine leading,after the creation of the C5'-C8 bond and a subsequent oxidation step,to the predominant formation of the 5'R diastereomer for both purine 5',8-cyclonucleosides. The reduced formation yield of the 4 tandem lesions in the presence of O-2 explains,at least partly,the low efficiency of radiation-induced yields of the purine 5',8-cyclo-2'-deoxyribonucleosides in cellular DNA,which are about two orders of magnitude lower than the previously reported data obtained from HPLC-MS analysis.