DNA Adducts of the Carcinogen Acetaldehyde

描述：(申请人提供)国际研究机构 癌症认为乙醛“可能对人类致癌”，而 美国部门美国卫生与公众服务部表示，乙醛是“合理的 预期是人类致癌物质。“这些评估是基于 令人信服的致癌研究清楚地表明乙醛 给大鼠和仓鼠服用时会引起呼吸道肿瘤 吸气。人类很有可能广泛接触到 乙醛。香烟烟雾中的乙醛含量约为1毫克。 香烟，其浓度远远大于其他致癌物质的浓度 如苯并[a]芘或烟草特有亚硝胺，被广泛认为是 对于吸烟者来说，这是癌症的重要原因。乙醛是主要的代谢物 在饮酒的人体内可以达到显著的浓度 酒精饮料，尤其是如果它们缺乏某些形式的 乙醛脱氢酶。乙醛被认为是几起 与饮酒有关的癌症类型。人类暴露于 乙醛也可以出现在职业和环境环境中。在……里面 尽管人类广泛接触这种致癌物质，但人们对其知之甚少。 DNA加合物，这可能是其致癌活性的中心。我们有 最近表征了几种乙醛的DNA加合物，包括希夫 碱N_2-亚乙基脱氧鸟苷，两个非对映异构体L，N_2-丙基脱氧鸟苷 加合物、三个非对映异构体N_2-二甲基二氧基脱氧鸟苷加合物和一个 链间G-G交联剂。这些数据有望开辟新的 对乙醛致癌的认识。因此，我们建议延长 本提案中的这些研究。我们的具体目标是：1)发展 乙醛-DNA加合物的灵敏质谱学检测方法。这些 方法将应用于乙醛-DNA加合物的体外分析， 暴露于乙醛的实验动物和人类(特定目标2、4、 和5)；2)乙醛-DNA的形成和立体化学 体外加合物，使用乙醛浓度很可能是 体内实现；3)合成含有 乙醛-DNA交联物并研究其修复和致突变性； 4)定量测定乙醛-DNA加合物在大鼠体内的形成和存留 或暴露在乙醛或乙醇中的小鼠；5)定量乙醛-DNA 暴露于乙醛的人的白细胞中的加合物。这些研究 将在吸烟者、非吸烟者、临时饮酒者和有 酒精依赖。这里提出的研究结果将提供 关键数据，这将是检验我们的假设的框架 乙醛是一种人类致癌物质。

DESCRIPTION: (PROVIDED BY APPLICANT) The International Agency for Research on Cancer evaluates acetaldehyde as "possibly carcinogenic to humans" while the U.S. Dept. of Health and Human Services states that acetaldehyde is "reasonably anticipated to be a human carcinogen." These evaluations are based on convincing carcinogenicity studies that clearly demonstrate that acetaldehyde causes respiratory tract tumors in rats and hamsters when administered by inhalation. There is great potential for extensive human exposure to acetaldehyde. Cigarette smoke contains about 1 mg of acetaldehyde per cigarette, which is far greater than the concentrations of other carcinogens such as benzo[a]pyrene or tobacco-specific nitrosamines, widely assumed to be important as causes of cancer in smokers. Acetaldehyde is the major metabolite of ethanol and can reach significant concentrations in people who drink alcoholic beverages, especially if they are deficient in certain forms of aldehyde dehydrogenase. Acetaldehyde has been implicated as a cause of several cancer types associated with alcohol consumption. Human exposure to acetaldehyde can also occur in occupational and environmental settings. In spite of extensive human exposure to this carcinogen, little is known about its DNA adducts, which are likely central to its carcinogenic activity. We have recently characterized several DNA adducts of acetaldehyde including the Schiff base N2-ethylidenedeoxyguanosine, two diastereomeric l,N2-propanodeoxyguanosine adducts, three diastereomeric N2-dimethyldioxanyldeoxyguanosine adducts, and an interstrand G-G crosslink. These data promise to open new avenues of understanding of acetaldehyde carcinogenesis. Therefore, we propose to extend these studies in the present proposal. Our specific aims are: 1) Develop sensitive mass spectrometric methods to detect acetaldehyde-DNA adducts. These methods will be applied for analysis of acetaldehyde-DNA adducts in vitro, in laboratory animals exposed to acetaldehyde, and in humans (Specific Aims 2, 4, and 5); 2) Investigate the formation and stereochemistry of acetaldehyde-DNA adducts in vitro, using concentrations of acetaldehyde that are likely to be achieved in vivo; 3) Synthesize oligonucleotides containing the acetaldehyde-DNA crosslink adduct and investigate its repair and mutagenicity; 4) Quantify the formation and persistence of acetaldehyde-DNA adducts in rats or mice exposed to acetaldehyde or ethanol; 5) Quantify acetaldehyde-DNA adducts in white blood cells of humans exposed to acetaldehyde. These studies will be carried out in smokers, non-smokers, casual drinkers, and people with alcohol dependence. The results of the research proposed here will provide critical data, which will be the framework for testing our hypothesis that acetaldehyde is a human carcinogen.