DNA Adducts of the Carcinogen Acetaldehyde

致癌物乙醛的 DNA 加合物

• 批准号: 7799327
• 负责人: STEPHEN S HECHT
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-18 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799327
• 关键词: 2-butenal; A/J Mouse; Acetaldehyde; Acrolein; Air; Alcohol consumption; Alcohol dehydrogenase; Benzo(a)pyrene; Biological; Breathing; Bypass; Carcinogens; Cells; Chinese People; Cotinine; DNA; DNA Adducts; DNA-Directed DNA Polymerase; Data; Diet; Environment; Ethanol; Genes; Genetic Polymorphism; Goals; Grant; Head and neck structure; Health; Human; In Vitro; Laboratory Animals; Leukocytes; Lung; Malignant Neoplasms; Methods; Nitrosamines; Nose; Polymerase; Process; Property; Role; Services; Smoker; Testing; Tissues; Tobacco; Tumorigenicity; Woman; adduct; aldehyde dehydrogenases; cigarette smoking; cigarette smoking; cooking; crosslink; drinking; human tissue; larynx Carcinoma; non-smoker; non-smoking; programs; repaired; urinary

DESCRIPTION (provided by applicant): According to the U.S. Dept. of Health and Human Services, acetaldehyde is "reasonably anticipated to be a human carcinogen". When administered to laboratory animals by inhalation, acetaldehyde produces nasal and laryngeal carcinomas. Acetaldehyde occurs widely in the human environment, is a major constituent of cigarette smoke, and is the main metabolite of ethanol. Levels of acetaldehyde in the environment may increase with the introduction of ethanol-containing fuels. DNA adducts are critical in the carcinogenic process. In this program, we have identified DNA adducts of acetaldehyde including the major adduct N2- ethylidene-dGuo (adduct 1), the 1,A/2-propano-dGuo adducts 3 which are also formed from crotonaldehyde, and a related interstrand cross-link (adduct 4). We have developed highly sensitive mass spectrometric methods to quantify adducts 1 and 3 in human tissues. We have demonstrated that adduct 1 can be quantified in low microgram amounts of DNA, that it is an endogenous DNA adduct, and that its levels are influenced by cigarette smoking. We have also shown that adduct 3 is present in human lung DNA and has miscoding potential in human cells. In this renewal application, we propose to continue our studies on acetaldehyde DNA adducts to test our overall hypothesis that they are involved as causes of human cancer, particularly of the lung, and head and neck. Our goal is to investigate the occurrence in humans and the biological significance of acetaldehyde DNA adducts. Our specific aims are: 1. Quantify levels of adducts 1, 3, and the related acrolein-derived adduct 5 in human lung DNA from current smokers (confirmed by urinary cotinine) and compare levels of these adducts to those derived from benzo[a]pyrene (BaP) and tobacco-specific nitrosamines in the same tissues. 2a. Determine the influence of polymorphisms in alcohol dehydrogenase (ADH1C) and aldehyde dehydrogenase (ALDH2) genes on levels of adduct 1 in leukocyte DNA of non-smokers who consume alcohol. b. Quantify levels of adduct 1 in leukocyte DNA of non-smoking, non-drinking Chinese women who regularly engage in wok cooking compared to those who do not. 3. Investigate the genotoxic properties of adduct 1 in cells, and by studies in A/J mice which compare adduct formation and tumorigenicity of compounds that do or do not generate acetaldehyde. 4. Investigate the mechanism of translesion synthesis across adduct 3 and "half-excised" interstrand cross-links. We have shown that these adducts are bypassed by mammalian DNA polymerases in cells. Here we propose to identify those polymerases and characterize the translesion synthesis by in vitro and cellular approaches. These studies will provide critical data on the occurrence and biological significance of acetaldehyde DNA adducts and their possible role in human cancer.

描述（由申请人提供）：根据美国部门。根据美国卫生与公众服务部的报告，乙醛“被合理地认为是一种人类致癌物”。当通过吸入给予实验室动物时，乙醛产生鼻腔和喉癌。乙醛广泛存在于人类环境中，是香烟烟雾的主要成分，也是乙醇的主要代谢产物。环境中的乙醛水平可能会随着含乙醇燃料的引入而增加。DNA加合物在致癌过程中至关重要。在该程序中，我们已经鉴定了乙醛的DNA加合物，包括主要加合物N2-亚乙基-dGuo（加合物1）、也由巴豆醛形成的1，A/2-丙氧基-dGuo加合物3以及相关的链间交联（加合物4）。我们已经开发出高灵敏度的质谱方法来定量加合物1和3在人体组织中。我们已经证明，加合物1可以在低微克量的DNA中定量，它是一种内源性DNA加合物，其水平受吸烟的影响。我们还表明，加合物3存在于人肺DNA中，并在人细胞中具有错误编码的可能性。在这个更新申请中，我们建议继续我们对乙醛DNA加合物的研究，以测试我们的总体假设，即它们是人类癌症的原因，特别是肺癌和头颈癌。我们的目标是研究乙醛DNA加合物在人类中的发生及其生物学意义。我们的具体目标是：1.定量当前吸烟者的人肺DNA中加合物1、3和相关丙烯醛衍生加合物5的水平（通过尿可替宁证实），并将这些加合物的水平与相同组织中苯并[a]芘（BaP）和烟草特异性亚硝胺衍生的加合物的水平进行比较。2a.确定酒精脱氢酶（ADH 1C）和乙醛脱氢酶（ALDH 2）基因多态性对饮酒的非吸烟者白细胞DNA中加合物1水平的影响。B.定量加合物1水平的白细胞DNA的不吸烟，不喝酒的中国妇女谁经常从事炒锅做饭相比，那些谁不。3.研究加合物1在细胞中的遗传毒性，并通过A/J小鼠研究比较产生或不产生乙醛的化合物的加合物形成和致瘤性。4.研究跨加合物3和“半切除”链间交联的跨损伤合成机制。我们已经表明，这些加合物绕过哺乳动物DNA聚合酶在细胞中。在这里，我们建议确定这些聚合酶和表征的translesion合成体外和细胞的方法。这些研究将为乙醛DNA加合物的发生和生物学意义及其在人类癌症中的可能作用提供关键数据。