Carmella S G, Borukhova A, Desai D, Hecht S S
American Health Foundation, Valhalla, NY 10595, USA.
Carcinogenesis. 1997 Mar;18(3):587-92. doi: 10.1093/carcin/18.3.587.
Carcinogenic tobacco-specific nitrosamines are present in tobacco products and are believed to play a significant role in human cancers associated with tobacco use. Additional amounts of tobacco-specific nitrosamines could be formed endogenously. We tested this hypothesis by treating rats with nicotine and sodium nitrite and analyzing their urine. Initially, we treated groups of rats with (S)-nicotine (60 micromol/kg) and NaNO2 (180 micromol/kg), (S)-nicotine alone, NaNO2 alone or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 12 nmol/kg) by gavage twice daily for 4 days. We collected urine and analyzed for two metabolites of NNK; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide. We did not detect these metabolites in the urine of rats treated with nicotine alone or nicotine plus NaNO2, indicating that endogenous conversion of nicotine to NNK did not occur. However, the urine did contain N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB) and N'-nitrosoanatabine (NAT). Analysis of the (S)-nicotine used in this experiment demonstrated that it contained trace amounts of nornicotine, anabasine and anatabine. In a second experiment, we used an identical protocol to compare the endogenous nitrosation of this (S)-nicotine with that of synthetic (R,S)-nicotine, which did not contain detectable amounts of nornicotine, anabasine or anatabine. NNN (0.53 x 10(-3)% of nicotine dose), NAB (0.68%) and NAT (2.1%) were detected in the urine of the rats treated with the (S)-nicotine and NaNO2. NNN (0.47 x 10(-3)% of dose), but not NAB or NAT, was present in the urine of the rats treated with synthetic (R,S)-nicotine and NaNO2. NNN probably formed via nitrosation of metabolically formed nornicotine. These results demonstrate for the first time that endogenous formation of tobacco-specific nitrosamines occurs in rats treated with tobacco alkaloids and NaNO2. The potential significance of the results with respect to nitrosamine formation in people who use tobacco products or nicotine replacement therapy is discussed.
致癌性烟草特有亚硝胺存在于烟草制品中，据信在与烟草使用相关的人类癌症中起重要作用。烟草特有亚硝胺还可能在体内内源性形成。我们通过用尼古丁和亚硝酸钠处理大鼠并分析其尿液来验证这一假设。最初，我们每天两次通过灌胃给大鼠组施用（S）-尼古丁（60微摩尔/千克）和亚硝酸钠（180微摩尔/千克）、单独的（S）-尼古丁、单独的亚硝酸钠或4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK，12纳摩尔/千克），持续4天。我们收集尿液并分析NNK的两种代谢产物；4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇及其葡萄糖醛酸苷。我们在单独用尼古丁或尼古丁加亚硝酸钠处理的大鼠尿液中未检测到这些代谢产物，这表明尼古丁未内源性转化为NNK。然而，尿液中确实含有N'-亚硝基去甲烟碱（NNN）、N'-亚硝基新烟草碱（NAB）和N'-亚硝基假木贼碱（NAT）。对本实验中使用的（S）-尼古丁分析表明，它含有痕量的去甲烟碱、新烟草碱和假木贼碱。在第二个实验中，我们使用相同方案比较这种（S）-尼古丁与合成（R,S）-尼古丁（不含有可检测量的去甲烟碱、新烟草碱或假木贼碱）的内源性亚硝化作用。在用（S）-尼古丁和亚硝酸钠处理的大鼠尿液中检测到NNN（占尼古丁剂量的0.53×10⁻³%）、NAB（0.68%）和NAT（2.1%）。在用合成（R,S）-尼古丁和亚硝酸钠处理的大鼠尿液中存在NNN（占剂量的0.47×10⁻³%），但不存在NAB或NAT。NNN可能是通过代谢形成的去甲烟碱的亚硝化作用形成的。这些结果首次证明在用烟草生物碱和亚硝酸钠处理的大鼠中发生了烟草特有亚硝胺的内源性形成。讨论了这些结果对于使用烟草制品或尼古丁替代疗法的人群中亚硝胺形成的潜在意义。
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