2′-Deoxyguanosine, 2′-deoxycytidine, and 2′-deoxyadenosine adducts resulting from the reaction of tetrahydrofuran with DNA bases
2′-Deoxyguanosine, 2′-deoxycytidine, and 2′-deoxyadenosine adducts resulting from the reaction of tetrahydrofuran with DNA bases
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DOI：
10.1021/tx060033d
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发表时间：
2006-07-17
影响因子：
4.1
通讯作者：
Loureiro, A. Paula M.
中科院分区：
文献类型：
--
作者：
Hermida, Silvia A. S.;Possari, Ediliz P. M.;Loureiro, A. Paula M.
最近的一项研究表明，广泛使用的溶剂四氢呋喃（THF）在实验动物中具有致癌性。尽管THF具有致癌活性，但关于THF的细胞毒性、生物分子损伤和遗传毒性的信息却很少。本文描述了氧化THF与2'-脱氧鸟苷（dGuo-THF 1和dGuo-THF 2）、2'-脱氧腺苷（ddo -THF）和2'-脱氧胞苷（dCyd-THF）反应产生的加合物的结构表征。通过反相高效液相色谱法从体外反应中分离出加合物，并通过光谱测量对其进行了全面表征。以NaBH4还原加合物得到的稳定衍生物（dGuo-THF 1、dCyd-THF和ddo - thf）和稳定加合物dGuo-THF 2为标准，通过HPLC/ESI/MSMS优化DNA加合物检测的色谱分离。利用这种方法，我们成功地检测了小牛胸腺DNA中与氧化THF反应的四种加合物。本研究还提供了证据，证明大鼠肝微粒体单氧化酶将THF氧化为能够破坏DNA分子的活性亲电化合物，当将NADPH添加到THF/微粒体/dGuo培养混合物中时，加合物dGuo-THF 1水平显着增加。我们的数据表明dna -四氢呋啶加合物可能是四氢呋啶暴露的毒理学效应的促成因素。
A recent study showed that tetrahydrofuran (THF), a widely used solvent, is carcinogenic in experimental animals. Despite its carcinogenic activity, there is a paucity of information regarding cellular toxicity, biomolecular damage, and genotoxicity induced by THF. We describe here the structural characterization of adducts produced by the reaction of oxidized THF with 2'-deoxyguanosine (dGuo-THF 1 and dGuo-THF 2), 2'-deoxyadenosine (dAdo-THF), and 2'-deoxycytidine (dCyd-THF). Adducts were isolated from in vitro reactions by reverse-phase HPLC and fully characterized on the basis of spectroscopic measurements. The stable derivatives obtained by the reduction of adducts with NaBH4 ( the case of dGuo-THF 1, dCyd-THF, and dAdo-THF) and the stable adduct dGuo-THF 2 were used as standards for optimization of chromatographic separations for adduct detection in DNA through HPLC/ESI/MSMS. Using this methodology, we successfully detected the four adducts in calf thymus DNA reacted with oxidized THF. The present study also provides evidence that rat liver microsomal monooxigenases oxidize THF to the reactive electrophilic compounds that are able to damage the DNA molecule, as indicated by a significant increase in adduct dGuo-THF 1 level when NADPH was added to the THF/ microsomes/dGuo incubation mixtures. Our data point to DNA-THF adducts as possible contributing factors to the toxicological effects of THF exposure.