Effect of the XRCC1 codon 399 polymorphism on the repair of vinyl chloride metabolite-induced DNA damage.
Effect of the XRCC1 codon 399 polymorphism on the repair of vinyl chloride metabolite-induced DNA damage.
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DOI：
10.4103/1477-3163.56290
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发表时间：
2009
影响因子：
--
通讯作者：
Brandt-Rauf PW
中科院分区：
文献类型：
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作者：
Li Y;Long C;Lin G;Marion MJ;Freyer G;Santella RM;Brandt-Rauf PW
最近的流行病学证据表明，常见的多态性在氨基酸残基399的X射线交叉互补-1（XRCC1）蛋白，碱基切除修复（BER）途径的DNA损伤的关键组成部分，发挥了显着的作用，在遗传变异的个人方面的诱变性损伤，他们的经验暴露于致癌物质氯乙烯（VC）。本研究的目的是为这些流行病学观察的生物学可接受性提供支持，实验数据来自于暴露于环氧氯乙烷（CEO）（VC的活性代谢产物）后的XRCC1多态性纯合野生型或纯合变体个体的培养细胞系，测量修复前后诱导的乙烯基DNA加合物。来自7名VC工人的永生化淋巴母细胞系（4个纯合野生型和3个纯合399 XRCC1多态性变体）暴露于CEO，通过酶联免疫吸附测定（ELISA）测定暴露前和暴露后0、4、8和24 h的乙烯基腺苷（ε A）加合物水平。在暴露后8和24 h，变异细胞中的平均ε A加合物水平在统计学上显著高于野生型细胞（P <0.05），变异细胞中的总体平均修复效率为32%，而野生型细胞中为82%。这些结果与暴露个体中观察到的VC诱导的生物标志物类型的流行病学发现和所得肿瘤中发现的突变谱以及BER，特别是XRCC1，在这种致癌途径中发挥的关键作用一致。
Recent epidemiologic evidence suggests that the common polymorphism at amino acid residue 399 of the x-ray cross complementing-1 (XRCC1) protein, a key component of the base excision repair (BER) pathway for DNA damage, plays a significant role in the genetic variability of individuals in terms of the mutagenic damage they experience following exposure to the carcinogen vinyl chloride (VC). The aim of this study was to provide support for the biological plausibility of these epidemiologic observations with experimental data derived from cell lines in culture from individuals who were either homozygous wild-type or homozygous variant for this XRCC1 polymorphism following exposure to chloroethylene oxide (CEO), the active metabolite of VC, with measurement of the induced etheno-DNA adducts before and after repair. Immortalized lymphoblast cell lines from seven VC workers (four homozygous wild-type and three homozygous variant for the 399 XRCC1 polymorphism) were exposed to CEO, and etheno-adenosine (εA) adduct levels were determined by enzyme-linked immunosorbent assay (ELISA) pre-exposure and at 0, 4, 8 and 24 h following exposure. The average εA adduct levels were statistically significantly higher in the variant cells compared to the wild-type cells at 8 and 24 h following exposure (P< 0.05) with an overall average repair efficiency of 32% in the variant cells compared to 82% in the wild-type cells. These results are consistent with the epidemiologic findings of the types of VC-induced biomarkers observed in exposed individuals and the mutational spectra found in the resultant tumors as well as the key role that BER, especially XRCC1, plays in this carcinogenic pathway.