Nornicotine in smokeless tobacco as a precursor for carcinogen exposure

描述：烟草生物碱去甲烟碱是N '-亚硝基去甲烟碱（NNN）的前体，NNN是一种有效的烟草特异性致癌物。NNN被认为在烟草使用者的食管癌和口腔癌的诱导中起重要作用。去甲尼古丁以两种方式导致烟草使用者的NNN暴露。除了是烟草中NNN形成的前体之外，它还可以内源性地被亚硝化。烟草制品中存在的去甲烟碱的内源性亚硝化可发生在烟草使用者的口腔、胃或身体其他部位。这与无烟烟草产品的使用特别相关，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使用与口腔癌和食道癌的关联，迫切需要对无烟烟草产品中的去甲烟碱含量进行监管。美国食品和药物管理局（FDA）有权根据《家庭吸烟预防和烟草控制法》对有害和潜在有害的烟草成分进行监管。关于去甲尼古丁的内源性亚硝化程度与其在无烟产品中含量的函数关系的信息对于FDA对该烟草成分的充分监管至关重要。这项建议的目的是：（1）确定目前在美国销售的无烟产品中去甲尼古丁含量的变化。没有关于个别无烟品牌中去甲尼古丁含量的信息，目前在美国销售的产品之间的变化程度尚不清楚。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)目的：探讨无烟烟草使用者神经网络的内源性形成。无烟烟草使用者将被随机分配到一种不含烟草的草药鼻烟，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的生物标志物-将通过使用液相色谱串联质谱法测量这些受试者。该方法将允许特异性鉴别来自去甲烟碱内源性亚硝化的尿总NNN，与暴露于烟草制品中的NNN所产生的尿总NNN。将通过逐渐减少加入研究鼻烟中的同位素标记的去甲烟碱的量来研究去甲烟碱减少对内源性NNN形成程度的影响。这项研究的结果将提供非常重要的新信息，致癌亚硝胺NNN的内源性形成后，暴露于烟草使用的去甲尼古丁。了解这一过程对于充分监管烟草制品中的去甲尼古丁以最大限度地减少公众危害是绝对必要的。

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.