Time course of DNA adduct formation in peripheral blood granulocytes and lymphocytes after drinking alcohol
Time course of DNA adduct formation in peripheral blood granulocytes and lymphocytes after drinking alcohol
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DOI：
10.1093/mutage/ges008
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发表时间：
2012-07-01
期刊：
影响因子：
2.7
通讯作者：
Hecht, Stephen S.
中科院分区：
文献类型：
--
作者：
Balbo, Silvia;Meng, Lei;Hecht, Stephen S.
饮酒是头颈癌、结肠直肠癌、肝癌和女性乳腺癌的一个既定风险因素。乙醛，乙醇的主要代谢产物，被怀疑在酒精相关的致癌作用中起主要作用。乙醛与DNA结合，形成加合物。DNA加合物参与诱变和致癌作用。N-2-亚乙基脱氧鸟苷（N-2-ethylideneoxyguanosine，N-2-ethylidene-dGuo）是该反应中形成的主要加合物。研究表明，饮酒和这种DNA加合物的水平之间存在关联，这表明它可能用作研究酒精相关致癌作用的生物标志物。然而，没有关于饮酒后N-2-亚乙基-dGuo的形成和修复动力学的报道。因此，我们研究了在摄入增加剂量的酒精后的几个时间点，人外周血细胞DNA中N-2-亚乙基-dGuo的水平。招募了10名健康的非吸烟者，并要求他们除了研究剂量外戒酒。受试者每周服用一次测量剂量的酒精，持续3周，目标是增加血液酒精水平。在每次给药前和给药后的几个时间点采集血液，从粒细胞和淋巴细胞中分离DNA，并通过液相色谱-电喷雾电离-串联质谱法将N-2-亚乙基-dGuo定量为其NaBH3CN还原产物N-2-乙基脱氧鸟苷。在所有剂量后和两种细胞类型中均观察到N-2-亚乙基-dGuo显著增加。然而，有很大的个体内变异，表明有其他重要来源的这种加合物在外周血DNA。需要进一步的研究来更好地了解血细胞中N-2-亚乙基-dGuo的来源，它反映的暴露，以及它作为酒精遗传毒性作用标志物的潜在用途。
Alcohol consumption is an established risk factor for cancers of the head and neck, colorectum, liver and female breast. Acetaldehyde, the primary metabolite of ethanol, is suspected to play a major role in alcohol-related carcinogenesis. Acetaldehyde binds to DNA resulting in formation of adducts. DNA adducts are involved in mutagenesis and carcinogenesis. N-2-Ethylidenedeoxyguanosine (N-2-ethylidene-dGuo) is the major adduct formed in this reaction. Studies have shown an association between alcohol drinking and levels of this DNA adduct, suggesting its potential use as a biomarker for studying alcohol-related carcinogenesis. However, there are no reports on the kinetics of formation and repair of N-2-ethylidene-dGuo after alcohol consumption. Therefore, we investigated levels of N-2-ethylidene-dGuo in DNA from human peripheral blood cells at several time points after consumption of increasing doses of alcohol. Ten healthy non-smokers were recruited and asked to abstain from alcohol consumption except for the study doses. The subjects were given measured doses of alcohol once a week for 3 weeks, targeting increasing blood alcohol levels. Blood was collected at several time points before and after each dose, DNA was isolated from granulocytes and lymphocytes and N-2-ethylidene-dGuo was quantified as its NaBH3CN reduction product N-2-ethyldeoxyguanosine by liquid chromatography-electrospray ionisation-tandem mass spectrometry. Significant increases in N-2-ethylidene-dGuo were observed after all doses and in both cell types. However, there was substantial intraindividual variability, indicating that there are other important sources of this adduct in peripheral blood DNA. Further studies are needed to better understand the origins of N-2-ethylidene-dGuo in blood cells, the exposures it reflects, and thus its potential use as a marker of alcohol's genotoxic effects.