DNA Adducts of the Carcinogen Acetaldehyde

描述：（申请人提供）国际研究机构 癌症评估乙醛为“可能对人类致癌”， 美国部卫生与公众服务部指出，乙醛是“合理的”， 被认为是人类致癌物。“这些评估是基于 令人信服的致癌性研究清楚地表明，乙醛 在大鼠和仓鼠中， 吸入。人类广泛接触有毒物质的潜力巨大 乙醛香烟烟雾中含有约1毫克的乙醛， 香烟，这是远远大于其他致癌物质的浓度 如苯并[a]芘或烟草特有的亚硝胺，广泛认为是 是吸烟者患癌症的重要原因。乙醛是主要代谢产物 酒精的含量，在饮酒的人身上可以达到很高的浓度。 酒精饮料，特别是如果他们缺乏某些形式的 醛脱氢酶乙醛被认为是几种 与饮酒有关的癌症类型。人类接触 乙醛也可在职业和环境设置中出现。在 尽管人类广泛接触这种致癌物质，但对其 DNA加合物，这可能是其致癌活性的核心。我们有 最近鉴定了几种乙醛的DNA加合物，包括Schiff 碱基N2-亚乙基脱氧鸟苷，两种非对映异构体1，N2-丙氧鸟苷 加合物，三种非对映体N2-二甲基二氧杂环己烷脱氧鸟苷加合物，和一种 股间G-G交联。这些数据有望开辟新的途径， 了解乙醛致癌作用。因此，我们建议延长 这些研究在目前的建议。我们的具体目标是：1）发展 灵敏的质谱方法来检测乙酰丙酮-DNA加合物。这些 方法将应用于分析乙酰丙酮-DNA加合物在体外， 暴露于乙醛的实验室动物和人类（具体目标2，4， 2）研究乙酰丙酮-DNA的形成和立体化学 加合物在体外，使用浓度的乙醛，可能是 3）合成含有寡核苷酸的寡核苷酸， 乙酰丙酮-DNA交联加合物及其修复和致突变性研究; 4)定量大鼠中乙酰丙酮-DNA加合物的形成和持久性 或暴露于乙醛或乙醇的小鼠; 5）定量乙醛-DNA 暴露于乙醛的人的白色血细胞中的加合物。这些研究 将在吸烟者、非吸烟者、偶尔饮酒者和 酒精依赖本文提出的研究结果将提供 关键数据，这将是测试我们假设的框架， 乙醛是一种人类致癌物。

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.