Nornicotine Nitrosation in Saliva and Its Relation to Endogenous Synthesis of N′-Nitrosonornicotine in Humans
Nornicotine Nitrosation in Saliva and Its Relation to Endogenous Synthesis of N′-Nitrosonornicotine in Humans
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DOI：
10.1093/ntr/nts172
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发表时间：
2013-02-01
影响因子：
4.7
通讯作者：
Stepanov, Irina
中科院分区：
文献类型：
--
作者：
Knezevich, Aleksandar;Muzic, John;Stepanov, Irina
简介：我们最近报道，在一些口服尼古丁替代治疗产品的使用者中，尼古丁和/或去甲尼古丁可以内源性地形成一定量的致癌物 N'-亚硝基去甲尼古丁 (NNN)。虽然胃的酸性环境为亚硝化创造了最有利的条件，但在存在中性 pH 条件下催化亚硝化的细菌的情况下，这种反应也可能发生在口腔中。方法：为了检验口腔中可能发生内源性 NNN 形成的假设，我们研究了人唾液中尼古丁和降烟碱的亚硝化。为了具体鉴定 NNN 是否源自添加到唾液中的前体，我们将唾液样品与 [吡啶-D-4] 尼古丁和 [吡啶-D-4] 降烟碱（添加或不添加亚硝酸盐）一起孵育，随后通过液相色谱-串联质谱法分析 [吡啶-D-4] NNN。 结果：与尼古丁和降烟碱亚硝化的动力学研究一致，唾液与[吡啶-D-4]去甲尼古丁单独产生可检测量的[吡啶-D-4]NNN，而在与[吡啶-D-4]尼古丁和亚硝酸钠一起孵育的样品中仅发现痕量的[吡啶-D-4]NNN。将 10 名不吸烟志愿者的唾液样本与 [吡啶-D-4] 去甲尼古丁一起孵育，导致 8 个样本中形成 [吡啶-D-4] NNN，其产率范围为所添加生物碱的 0.003% 至 0.051%。结论：我们的结果表明，NNN 可以由人唾液中的去甲尼古丁形成，无需刻意添加任何其他物质。因此，烟草或尼古丁替代产品中存在的去甲尼古丁是一种致癌物质前体。
Introduction: We recently reported that certain amounts of the carcinogen N'-nitrosonornicotine (NNN) can be formed endogenously from nicotine and/or nornicotine in some users of oral nicotine replacement therapy products. Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH.Methods: To test the hypothesis that endogenous formation of NNN could occur in the oral cavity, we investigated nitrosation of nicotine and nornicotine in human saliva. To specifically identify NNN as derived from precursors added to saliva, we incubated saliva samples with [pyridine-D-4] nicotine and [pyridine-D-4] nornicotine, with and without the addition of nitrite, and subsequently analyzed [pyridine-D-4] NNN by liquid chromatography-tandem mass spectrometry.Results: Consistent with kinetic studies on nicotine and nornicotine nitrosation, incubation of saliva with [pyridine-D-4] nornicotine alone produced detectable amounts of [pyridine-D-4] NNN, whereas only traces of [pyridine-D-4] NNN were found in samples incubated with [pyridine-D-4] nicotine and sodium nitrite. Incubation of saliva samples from 10 nonsmoking volunteers with [pyridine-D-4] nornicotine resulted in the formation of [pyridine-D-4] NNN in 8 samples, with yields ranging from 0.003% to 0.051% of the added alkaloid.Conclusion: Our results demonstrate that NNN can be formed from nornicotine in human saliva without deliberate addition of any other substance. Therefore, nornicotine, as present in tobacco or in nicotine replacement products, is a carcinogen precursor.