BIOMARKERS OF NNK AND NNN METABOLISM IN HUMANS

在美国，癌症发展的最重要因素是 接触烟草制品。 最常见的接触途径是 烟草是随着无烟烟草使用的增加而产生的卷烟 近年来的产品。 其中最重要的致癌物质， 香烟烟雾和无烟烟草是烟草特有的亚硝胺 4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）和N '- 亚硝基去甲烟碱（NNN）。 这些亚硝胺存在于主流中， 每支香烟30-770纳克水平的侧流烟雾和无烟 烟草产品含量为100- 89，000 ppb。 NNK诱导的肿瘤 肺，气管和鼻腔在叙利亚金黄地鼠;肺，鼻 F_（344）大鼠腹腔、肝、胰及A.J小鼠肺组织的病理学改变。 一 NNN和NNK的混合物诱导F344大鼠的口腔肿瘤。 的 这些化合物在啮齿类动物中诱导肿瘤的器官特异性 与人类肿瘤的发病率相关。 如果一个战略， 预防与烟草有关的癌症将制定一项详细的 需要了解烟草致癌物的作用方式。 的 NNK的代谢活化通过α-碳羟基化发生， 两种途径之一。 第一个导致甲基化的形成 剂，第二次形成吡啶氧代丁基化剂。 我们 将开发和验证测定NNK代谢活化的方法 的NNN。 虽然一些指标，如尼古丁水平，已被 它们并不反映新陈代谢， 激活NNK或NNN。 NNK-DNA的GC-NICI-MS分析 加合物已经开发并将得到验证。 此外， 将开发和验证NNK-血红蛋白加合物的免疫测定。 这些试验将用于检测人样品的NNK和NNN加合物， DNA和血红蛋白 这些检测的可用性将使我们能够 确定DNA和血红蛋白加合物之间是否存在相关性。 这 信息是人类筛查程序所必需的，因为血红蛋白 加合物更容易测量，但DNA加合物在生物学上更 重要. 这些信息将使我们能够制定量化措施 比使用简单的风险度量更准确的风险度量， exposure.

The most important factor for cancer development in the United States is exposure to tobacco products. The most prevalent route of exposure to tobacco is cigarette smoking with increasing use of smokeless tobacco products in recent years. Among the most important carcinogens in cigarette smoke and smokeless tobacco are the tobacco specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'- nitrosonornicotine (NNN). These nitrosamines are present in mainstream and sidestream smoke at levels of 30-770 ng per cigarette and in smokeless tobacco products at levels of 100-89,000 ppb. NNK induces tumors of the lung, trachea and nasal cavity in Syrian golden hamsters; the lung, nasal cavity, liver an pancreas of F344 rats; and the lung in A.J mice. A mixture of NNN and NNK induced oral cavity tumors in F344 rats. The organospecificity of these compounds for tumor induction in rodents correlates with the incidence of tumors in humans. If a strategy for prevention of tobacco related cancers is to be developed a detailed understanding of the mode of action of tobacco carcinogens is needed. The metabolic activation of NNK occurs by alpha-carbon hydroxylation following one of two pathways. The first leads to the formation of methylating agent, the second to the formation of a pyridyloxobutylating agent. We will develop and validate assays to measure the metabolic activation of NNK and NNN. While a number of markers, such as nicotine levels, have been developed for monitoring exposure to tobacco they do not reflect metabolic activation of NNK or NNN. A sensitive GC-NICI-MS method for an NNK-DNA adduct has been developed and will be validated. In addition, an immunoassay for NNK-hemoglobin adducts will be developed and validated. These assays will be used to test human samples for NNK and NNN adducts of DNA and hemoglobin. The availability of these assays will allow us to determine if a correlation exists between DNA and hemoglobin adducts. This information is necessary for human screening programs since hemoglobin adducts are easier to measure but DNA adducts are biologically more important. This information will allow us to develop quantitative measures of risk which are more accurate than that possible using simple measures of exposure.