Role of GSTT1 deletion in DNA oxidative damage by exposure to polycyclic aromatic hydrocarbons in humans
Role of GSTT1 deletion in DNA oxidative damage by exposure to polycyclic aromatic hydrocarbons in humans
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DOI：
10.1002/ijc.22477
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发表时间：
2007-06-01
影响因子：
6.4
通讯作者：
Farmer, Peter
中科院分区：
文献类型：
--
作者：
Garter, Seymour;Taioli, Emanuela;Farmer, Peter
研究癌症易感性遗传变异机制的一种有效方法是使用与所研究基因机制相关的中间生化终点。我们研究了来自三个中欧城市的暴露于多环芳烃（PAH）的人群中，7个代谢基因位点的个体基因型对氧化DNA损伤标志物8-氧-7,8-二氢-2-脱氧鸟苷的影响。GSTT1纯合缺失变体对暴露于总多环芳烃和8种特定多环芳烃具有显著的保护作用，尽管这些化合物的作用程度和意义各不相同。使用分类敏感性分析来确定GSTT1缺失的频率在被证明对多环芳烃暴露的DNA损伤影响更有抵抗力的人群中明显高于最敏感的人群。越来越多的文献报道GSTT1缺失在与环境致癌相关的疾病和中间终点中的保护作用。这种作用的机制可能与PAH底物特异性有关，也可能与GSTT1基因在氧化应激诱导损伤途径中的其他功能有关。(c) 2007 Wiley-Liss, Inc。
A useful approach for studies on the mechanisms of genetic variation in cancer susceptibility is to use intermediary biochemical endpoints with mechanistic relevance to the genes under study. We examined the effects of individual genotype at seven metabolic gene loci on a marker of oxidative DNA damage, 8-oxo-7,8-dihydro-2-deoxyguanosine, in people exposed to polycyclic aromatic hydrocarbons (PAH) from three Central European cities. The GSTT1 homozygous deletion variant was associated with a significant protective effect for exposure to total PAHs and to eight specific PAHs, although the magnitude and significance of the effect varied among these compounds. Categorical sensitivity analysis was used to determine that the frequency of the GSTT1 deletion was significantly higher in people who proved to be more resistant to the DNA damaging effects of PAH exposure than in people who were the most sensitive. There is a growing literature on the protective effect of GSTT1 deletion in both disease and intermediary endpoints related to environmental carcinogenesis. The mechanism for this effect might be related to specific PAH substrate specificities, or could be related to other functions of GSTT1 gene in oxidative stress induced damage pathways. (c) 2007 Wiley-Liss, Inc.