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首页> 美国卫生研究院文献>Environmental Health Perspectives >Guanine and 78-dihydro-8-oxo-guanine-specific oxidation in DNA by chromium(V).
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Guanine and 78-dihydro-8-oxo-guanine-specific oxidation in DNA by chromium(V).

机译：铬（V）在DNA中的鸟嘌呤和78-二氢-8-氧代鸟嘌呤特异性氧化。

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摘要

The hexavalent oxidation state of chromium [Cr(VI)] is a well-established human carcinogen, although the mechanism of cancer induction is currently unknown. Intracellular reduction of Cr(VI) forms Cr(V), which is thought to play a fundamental role in the mechanism of DNA damage by this carcinogen. Two separate pathways of DNA damage, an oxidative pathway and a metal-binding pathway, have been proposed to account for the lesions observed in cell systems. We have used a model Cr(V) complex, N,N-ethylenebis(salicylidene-animato)oxochromium(V) [Cr(V)-Salen], to investigate the oxidative pathway of DNA damage and to elucidate the lesions generated from this oxidation process. Reaction of Cr(V)-Salen with synthetic oligonucleotides produced guanine-specific lesions that were not 8-oxo-2'-deoxyguanosine, based on the inability of iridium(IV) to further oxidize these sites. Oxidation products were identified using a 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-G) containing oligonucleotide to increase the yields of product for identification by electrospray ionization mass spectrometry. The guanine-based lesions observed by mass spectrometry corresponded to the lesions guanidinohydantoin and spiroiminodihydantoin. The effects of these Cr(V)-Salen-induced lesions on DNA replication fidelity was assayed using a polymerase-based misincorporation assay. These lesions produced G --> T transversion mutations and polymerase stops at levels greater than those observed for 8-oxo-G. These data suggest a model by which chromate can cause DNA damage leading to mutations and cancer.
机译：铬[Cr（VI）]的六价氧化态是一种公认​​的人类致癌物，尽管目前尚不清楚诱发癌症的机理。 Cr（VI）的细胞内还原形成Cr（V），据认为在此致癌物对DNA的损伤机理中起着基本作用。已经提出了两种单独的DNA损伤途径，即氧化途径和金属结合途径，以解释在细胞系统中观察到的损伤。我们已使用模型Cr（V）络合物N，N-亚乙基双（水杨基-芳香族）氧铬（V）[Cr（V）-Salen]来研究DNA损伤的氧化途径并阐明由此产生的病变氧化过程。基于铱（IV）无法进一步氧化这些位点，Cr（V）-Salen与合成寡核苷酸的反应产生了不是8-oxo-2'-deoxyguanosine的鸟嘌呤特异性损伤。使用含有寡核苷酸的7,8-二氢-8-氧代2'-脱氧鸟苷（8-氧代-G）鉴定氧化产物，以增加产物的收率，以通过电喷雾电离质谱法进行鉴定。通过质谱法观察到的基于鸟嘌呤的损伤对应于胍基乙内酰脲和螺胺二乙内酰脲。这些Cr（V）-Salen诱导的病变对DNA复制保真度的影响使用基于聚合酶的错误掺入测定法进行了测定。这些病变产生了G→T转换突变，聚合酶的终止水平高于8-oxo-G的水平。这些数据提出了一种模型，通过该模型铬酸盐可以引起DNA损伤，从而导致突变和癌症。

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