Acrylonitrile enhances H2O2-mediated DNA damage via nitrogen-centered radical formation
Acrylonitrile enhances H2O2-mediated DNA damage via nitrogen-centered radical formation
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DOI：
10.1021/tx010081s
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发表时间：
2001-10-01
影响因子：
4.1
通讯作者：
Kawanishi, S
中科院分区：
文献类型：
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作者：
Murata, M;Ohnishi, S;Kawanishi, S
丙烯腈（ACN）作为单体广泛应用于聚合物工业中。对暴露于乙腈的大鼠进行的致癌性研究表明，包括中枢神经系统神经胶质细胞瘤在内的肿瘤发病率增加，并且神经胶质细胞中 8-氧代-7,8-二氢-2'-脱氧鸟苷 (8-oxo-dG) 的产生增加。使用配备电化学检测器的高效液相色谱仪，我们发现 ACN 增强了 H2O2 和 Cu(II) 诱导的 8-oxo-dG 的形成，而 ACN 本身不会造成 DNA 损伤。 ACN的增强作用在双链DNA中比在单链DNA中更有效。使用 P-32 标记的 DNA 进行的实验表明，添加 ACN 会增强鸟嘌呤位点特异性 DNA 损伤，特别是 CTG 和 GGG 序列的 5' 位点，而 H2O2/Cu(II) 会诱导胸腺嘧啶、胞嘧啶和鸟嘌呤残基上的哌啶不稳定位点。使用α-(4-吡啶基-1-氧化物)-N-叔丁基硝酮的电子自旋共振光谱表明，在H2O2和Cu(II)存在下，ACN产生以氮为中心的自由基。人们认为 ACN 通过以氮为中心的自由基形成来增强 H2O2 介导的 DNA 损伤。我们将讨论与 ACN 致癌性表达相关的氧化 DNA 损伤增强作用的机制。
Acrylonitrile (ACN) is widely used as a monomer in the polymer industry. Studies on carcinogenicity in rats exposed to ACN showed increased incidences of tumors including glial cell tumors of central nervous system and increased production of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in glial cells. Using a high performance liquid chromatograph equipped with an electrochemical detector, we revealed that ACN enhanced the formation of 8-oxo-dG induced by H2O2 and Cu(II) whereas ACN itself did not cause DNA damage. The enhancing effect of ACN was much more efficient in the double-stranded DNA than that in the single-stranded DNA. Experiments with P-32-labeled DNA revealed that addition of ACN enhanced the site-specific DNA damage at guanines, particularly at 5'-site of the CTG and GGG sequences while H2O2/Cu(II) induced piperidine-labile sites at thymine, cytosine, and guanine residues. An electron spin resonance spectroscopy using alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone showed that a nitrogen-centered radical was generated from ACN in the presence of H2O2 and Cu(II). It is considered that ACN enhances H2O2-mediated DNA damage via nitrogen-centered radical formation. We will discuss the mechanism of the enhancing effect on oxidative DNA damage in relation to expression of ACN carcinogenicity.