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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 1200 万支无烟烟草（鼻烟或咀嚼烟草）当今美国的烟草使用者，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口腔癌的风险。无烟烟草使用者构成一个近乎独特的群体，因为他们代表了大量暴露于病毒的人群只含有一种或两种已知主要成分的高浓度混合物致癌物质。迄今为止已确定的重要致癌物是 4- (甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮(NNK)和亚硝基降烟碱 (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口腔内致癌。这两种化合物都需要氧化 N-亚硝基α碳原子的代谢，以发挥它们的致癌作用。如果这些化合物可以建立为人类致癌物，许多实际应用可能随之而来（例如，改变固化过程以降低 NNK 和 NNN 的水平，配制含有特定抑制剂的无烟烟草产品 NNK和NNN代谢，要求鼻烟制造商标明含量 NNK 和 NNN，改变某些生活方式因素（（例如饮食））可能会影响NNK和NNN等的代谢）。此外，摄入可以确定无烟烟草使用者中的 NNN 和 NNK，并且大量人类致癌的剂量反应曲线可以建立 - 一个具有大量应用的结果毒理学外推。虽然NNK和NNN成立了对实验动物有致癌作用，可经大鼠口服代谢组织，将它们确定为人类致癌物的关键环节是缺乏——它们尚未被证明可以被人类口服代谢组织。这个项目将解决这个问题。这些研究是计划将测量：1）人体口腔组织对 NNK 的生物转化（牙龈和颊组织匀浆）使用放射测定法监测甲醛和甲醇（两种 α-氧化代谢物，2）所选口腔组织样本的 K ad V，3) NNK 和 NNN 的代谢人类口腔组织中沙门氏菌的诱变剂。此外，一项关键活动（06-甲基鸟嘌呤-DNA 甲基转移酶）参与 DNA 修复 NNK 引起的损伤将在人体口腔组织中进行测量。最后，生活方式因素（例如吸烟、饮酒或使用无烟烟草）会与 NNK 或 NNN 的代谢率以及 MT 相关人体口腔组织，尝试识别危险因素或保护因素影响 NNK 和 NNN 的基因毒性作用。