Nornicotine in smokeless tobacco as a precursor for carcinogen exposure

描述：烟草生物碱去甲尼古丁是N‘-亚硝基烟碱(NNN)的前体，N’-亚硝基烟碱是一种烟草特有的致癌物质。NNN被认为在烟草使用者的食道癌和口腔癌的诱发中起着重要作用。去甲尼古丁通过两种方式导致烟草使用者接触NNN。除了是烟草中NNN形成的前体外，它还可能被内源亚硝化。烟草产品中存在的去甲尼古丁的内源性亚硝化作用可发生在烟草使用者的口腔、胃或身体其他部位。这与使用无烟烟草产品特别相关，无烟烟草产品是一种长期保存在口腔中的烟草，为去甲尼古丁亚硝化创造了有利条件。鉴于NNN的高致癌效力以及无烟烟草的使用与口腔和食道癌的关联，迫切需要对无烟烟草产品中去甲尼古丁的含量进行监管。根据《家庭吸烟预防和烟草控制法》，美国食品和药物管理局(FDA)有权监管有害和潜在有害的烟草成分。关于去甲尼古丁内源性亚硝化程度与其在无烟产品中含量的关系的信息，对于FDA对这种烟草成分的适当监管是至关重要的。这项建议的目的是：(1)确定目前在美国销售的无烟产品中降尼古丁含量的变化。目前没有关于单个无烟品牌降尼古丁含量的信息，目前市场上销售的美国产品之间的差异程度也是未知的。目标1将解决这一重要差距，并将为本提案的目标2提供关键信息。(2)探讨无烟烟民内源性NNN的形成。无烟烟草使用者将被随机分配到一种无烟草药鼻烟中，其中含有不同数量的稳定同位素标记的去甲尼古丁。同位素标记的尿总NNN-暴露于NNN的生物标记物-将在这些受试者中使用液相色谱-串联质谱仪进行测量。这一方法将允许通过内源性去甲尼古丁的亚硝化反应与烟草产品中暴露于NNN的尿中NNN的接触来具体识别尿总NNN。通过逐渐减少用于研究鼻烟的同位素标记的去甲尼古丁的量，来研究去甲尼古丁减少对内源性NNN形成程度的影响。这项研究的结果将为烟草使用中接触去甲尼古丁时致癌亚硝胺NNN的内源性形成提供极其重要的新信息。了解这一过程对于适当管制烟草产品中的去甲尼古丁，以最大限度地减少对公众的危害是绝对必要的。

DESCRIPTION: The tobacco alkaloid nornicotine is a precursor to N'-nitrosonornicotine (NNN), a potent tobacco-specific carcinogen. NNN is believed to play an important role in the induction of esophageal and oral cavity cancers in tobacco users. Nornicotine contributes to NNN exposure in tobacco users in two ways. In addition to being a precursor to NNN formation in tobacco, it may also be nitrosated endogenously. Endogenous nitrosation of nornicotine that is present in tobacco products can occur in the oral cavity, in the stomach, or elsewhere in the body of tobacco users. This is particularly relevant to the use smokeless tobacco products - a form of tobacco that is kept in the oral cavity for prolonged periods of time, creating favorable conditions for nornicotine nitrosation. Given the high carcinogenic potency of NNN and the association of smokeless tobacco use with oral and esophageal cancers, regulation of nornicotine content in smokeless tobacco products is urgently needed. The Food and Drug Administration (FDA) has authority to regulate harmful and potentially harmful tobacco constituents under the Family Smoking Prevention and Tobacco Control Act. The information on the extent of endogenous nitrosation of nornicotine as a function of its content in smokeless products is crucial for the adequate regulation of this tobacco constituent by the FDA. Aims of this proposal are: (1) to determine the variation of nornicotine content in smokeless products currently marketed in the U.S. There is no information on nornicotine content in individual smokeless brands, and the extent of variation among the currently marketed U.S. products is unknown. Aim 1 will address this important gap and will also provide critical information for Aim 2 of this proposal. (2) To investigate the endogenous formation of NNN in smokeless tobacco users. Smokeless tobacco users will be randomized to a tobacco-free herbal snuff containing various amounts of stable isotope-labeled nornicotine added to it. Isotope-labeled urinary total NNN - a biomarker of exposure to NNN - will be measured in these subjects by using liquid chromatography-tandem mass- spectrometry. This methodology will allow for specific identification of urinary total NNN from endogenous nitrosation of nornicotine, versus that resulting from exposure to NNN in tobacco products. The effect of nornicotine reduction on the extent of endogenous NNN formation will be studied by gradually decreasing the amount of isotope-labeled nornicotine added to study snuff. The results of this study will provide extremely important new information on the endogenous formation of the carcinogenic nitrosamine NNN upon exposure to nornicotine from tobacco use. An understanding of this process is absolutely necessary for the adequate regulation of nornicotine in tobacco products with the purpose of minimizing public harm.