SMOKELESS TOBACCO CARCINOGENESIS AND ORAL TISSUE

无烟烟草致癌和口腔组织

基本信息

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
项目类别：
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

项目摘要

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.

有超过一千万的无烟烟草（鼻烟或咀嚼如今，美国的烟草用户，其中许多年轻。流行病学研究表明，无烟烟草的使用大大增加了口腔癌的风险。无烟烟草用户构成一个几乎独特的群体，因为它们代表了大量人口高水平的混合物，仅包含一个或两个主要已知的混合物致癌物。到目前为止，重要的致癌物是4- （甲基硝基氨基氨基氨基）-1-（3-吡啶基）-1-丁酮（NNK）和硝基诺替氨酸（NNN）（两者都是香烟烟的组成部分），目前的证据表明前者更有可能口腔中的致癌。两种化合物都需要氧化碳原子α上的代谢，施加N-硝基的组他们的致癌作用。如果这些化合物可以确定为人类的致癌物，可能会有许多实际应用（例如，改变固化过程以降低NNK和NNN的水平，制定无烟烟草产品以包含特定抑制剂 NNK和NNN代谢，要求鼻烟制造商表明水平 nnk和nnn，改变了某些生活方式因素（（例如饮食））可能影响NNK和NNN等的代谢）。另外，摄入量可以确定无烟烟草使用者中的nnn和nnk，并且可以确定大量人类癌变的剂量反应曲线可以建立 - 有大量应用的结果毒理学外推。尽管建立了NNK和NNN 实验动物中的致癌物，可以通过大鼠口服代谢组织，作为人类致癌物建立它们的关键联系是缺乏 - 尚未证明人口腔代谢组织。该项目将解决这个问题。研究计划将测量：1）人类口腔组织对NNK的生物转化（牙龈和颊组织匀浆）使用辐射测定法，该测定法监测甲醛和甲醇（两个α-氧化代谢产物，2） K AD V用于选定的口腔组织样品，3）NNK和NNN的代谢人类口腔组织中沙门氏菌中的诱变剂。另外，关键活动（06-甲基鸟嘌呤-DNA甲基转移酶）参与DNA的修复 NNK诱导的损害将在人口腔组织中测量。最后，生活方式因素（例如吸烟，酒精或无烟烟草使用）将与NNK或NNN的代谢率相关，并与MT相关人口腔组织，尝试识别危险因素或保护因素影响NNK和NNN的遗传毒性作用。