BIOMARKERS OF NNK AND NNN METABOLISM IN HUMANS

在美国，癌症发展最重要的因素是 接触烟草产品。最普遍的接触途径是 烟草是随着无烟烟草使用量的增加而吸烟的现象 近几年来的产品。最重要的致癌物质之一是 香烟烟雾和无烟烟草是烟草特有的亚硝胺 耐克(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone)和N‘- 亚硝基烟碱(NNN)。这些亚硝胺存在于主流和 侧流烟雾水平为每支香烟30-770 ng，无烟情况下 100-89,000 ppb的烟草产品。NNK诱导人卵巢肿瘤 叙利亚金黄地鼠的肺、气管和鼻腔；肺、鼻腔 F344大鼠的空肠、肝脏和胰腺；A.J小鼠的肺。一个 NNN和NNK混合液诱发F344大鼠口腔肿瘤。这个 这些化合物对啮齿动物诱发肿瘤的器官特异性 与人类肿瘤的发病率相关。如果一项战略是 烟草相关癌症的预防正在制定一项详细的 需要了解烟草致癌物的作用方式。这个 NNK的代谢激活是通过以下的α-碳羟化来实现的 两条路中的一条。第一种导致甲基化的形成 助剂中，第二种要形成一种吡氧丁基化剂。我们 将开发和验证测试方法来测量NNK的代谢活性 和NNN。虽然一些标记物，如尼古丁水平， 它们是为监测烟草暴露而开发的，并不反映代谢 激活NNK或NNN。灵敏的NNK-DNA的GC-NICI-MS检测方法 加合物已经开发出来，并将得到验证。此外，一个 将开发和验证NNK-血红蛋白加合物的免疫分析方法。 这些检测方法将用于检测人体样本中的NNK和NNN加合物。 DNA和血红蛋白。这些化验结果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 由于血红蛋白，人类筛查程序需要信息 加合物更容易测量，但DNA加合物在生物学上更 很重要。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 曝光。

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.