SMOKELESS TOBACCO CARCINOGENESIS AND ORAL TISSUE

无烟烟草致癌和口腔组织

• 批准号: 2131437
• 负责人: JOSEPH B GUTTENPLAN
• 金额: $ 3.66万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2131437
• 关键词: DNA damage; DNA repair; Salmonella; aerobiosis; biotransformation; chemical carcinogen; chemical carcinogenesis; disease /disorder proneness /risk; enzyme activity; formaldehyde; guanine; high performance liquid chromatography; human subject; methanol; methyltransferase; mutagens; nicotine; nitrosamines; oral pharyngeal neoplasm; radioassay; smokeless tobacco; tissue /cell culture

There are over twelve million smokeless tobacco (snuff or chewing tobacco) users in the U.S. today, many of them young. Epidemiological studies have indicated that smokeless tobacco usage greatly increases the risk for cancer of the oral cavity. Smokeless tobacco users constitute a nearly unique group in that they represent a large population exposed to high levels of a mixture that contains only one or two major known carcinogens. The important carcinogens thus far identified are 4- (methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) and nitrosonornicotine (NNN), (both are also components of cigarette smoke), with current evidence suggesting that the former is more likely to be carcinogenic in the oral cavity. Both compounds require oxidative metabolism at the carbon atoms alpha to the N-nitroso group to exert their carcinogenic effects. If these compounds can be established as carcinogens in humans, a number practical applications might follow (e.g., altering the curing process to reduce levels of NNK and NNN, formulating smokeless tobacco products to contain specific inhibitors of NNK and NNN metabolism, requiring snuff manufacturers to indicate levels of NNK and NNN, altering certain lifestyle factors ((e.g. diet)) that might affect metabolism of NNK and NNN, etc.). In addition, intake of NNN and NNK among smokeless tobacco users could be determined, and the dose-response curve for carcinogenesis in a large population of humans could be established - a result with considerable application for toxicological extrapolations. Although NNK and NNN are established carcinogens in experimental animals, and can be metabolized by rat oral tissue, a critical link in establishing them as carcinogens in humans is lacking- they have not been shown to be metabolized by human oral tissues. This project will address that problem. The studies which are planned will measure: 1) biotransformation of NNK by human oral tissue (gingival and buccal tissue homogenates) using a radiometric assay which monitors formaldehyde and methanol (two alpha-oxidative metabolites, 2) K ad V for selected oral tissue samples, 3) metabolism of NNK and NNN to mutagens in Salmonella by human oral tissue. In addition, a key activity (06-methylguanine-DNA methyltransferase) involved in the repair of DNA damage induced by NNK, will be measured in human oral tissue. Finally, lifestyle factors (e.g. smoking, alcohol or smokeless tobacco usage) will be correlated with rates of metabolism of NNK or NNN, and with MT by human oral tissue, to try and identify risk factors or protective factors affecting genotoxic effects of NNK and NNN.

世界上有超过1200万种无烟烟草（鼻烟或嚼烟 美国的烟草使用者，其中许多是年轻人。 流行病学 研究表明，无烟烟草的使用大大增加了 患口腔癌的风险。 无烟烟草使用者构成 一个几乎独特的群体，因为他们代表了一个庞大的人口暴露 只含有一种或两种主要已知的 致癌物质。 目前已知的主要致癌物有4种， （甲基亚硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK）和 亚硝基去甲烟碱（NNN），（两者也是香烟烟雾的成分）， 目前的证据表明，前者更有可能是 在口腔中致癌。 这两种化合物都需要氧化 N-亚硝基α位碳原子上的代谢发挥作用 它们的致癌作用。 如果这些化合物可以被确定为 人类致癌物质，一些实际应用可能随之而来 (e.g.,改变固化过程以降低NNK和NNN的水平， 配制无烟烟草产品以含有特定的 NNK和NNN代谢，要求鼻烟制造商注明水平 NNK和NNN，改变某些生活方式因素（例如饮食）， 可能影响NNK和NNN的代谢等）。 此外， 可以确定无烟烟草使用者的NNN和NNK， 大人群致癌作用的剂量-反应曲线 可以建立-一个结果与相当大的应用程序， 毒理学推断。 虽然NNK和NNN已经建立， 致癌物质在实验动物中，并可通过大鼠口服代谢 组织，在建立他们作为人类致癌物的一个关键环节， 缺乏-它们没有被证明是由人类口服代谢 组织中 这个项目将解决这个问题。 这些研究 计划将测量：1）NNK通过人口腔组织的生物转化 （牙龈和口腔组织匀浆）使用放射性测定， 监测甲醛和甲醇（两种α-氧化代谢产物，2） 3）NNK和NNN的代谢， 沙门氏菌中的诱变剂。 此外，一项重要活动 （06-甲基鸟嘌呤-DNA甲基转移酶）参与DNA的修复 将在人口腔组织中测量NNK诱导的损伤。 最后， 生活方式因素（如吸烟、饮酒或使用无烟烟草）将 与NNK或NNN的代谢率相关，并与MT相关， 人类口腔组织，试图识别风险因素或保护因素， 影响NNK和NNN的遗传毒性作用。