Schuller H M, Orloff M
Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville 37996, USA.
Biochem Pharmacol. 1998 May 1;55(9):1377-84. doi: 10.1016/s0006-2952(97)00651-5.
Lung cancer demonstrates a strong etiologic association with smoking. Of the two most common histologic lung cancer types, small cell carcinoma (SCLC) is found almost exclusively in smokers, whereas peripheral adenocarcinoma (PAC) also develops in a significant number of nonsmokers. N'-Nitrosonornicotine (NNN) and 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nicotine-derived nitrosamines, are potent lung carcinogens contained in tobacco products. Because of the structural similarity of NNN and NNK with nicotine, we hypothesized that these carcinogens are ligands for nicotinic acetylcholine receptors (nAChRs). Using cell lines derived from human small cell lung carcinoma and pulmonary adenocarcinoma with the site-selective ligands alpha-bungarotoxin (alpha-BTX) and epibatidine (EB) in receptor binding and cell proliferation assays, we found that SCLC expressed neuronal nicotinic receptors with high affinity to alpha-BTX, whereas PAC cells expressed nicotinic receptors with high affinity to EB. NNK bound with high affinity to alpha-BTX-sensitive nAChRs in SCLC cells, while NNN bound with high affinity to EB sensitive nAChRs in PAC cells. The affinity of each nitrosamine to these receptors was several orders of magnitude greater than that of nicotine. NNK stimulated the proliferation of SCLC cells via this mechanism. Our findings suggest that NNK may contribute to the genesis of SCLC in smokers via chronic stimulation of the alpha BTX-sensitive nAChR-subtype expressed in these cells. Both nitrosamines may also contribute to a host of nicotine-related diseases that are currently thought to be caused by the chronic interaction of nicotine with nAChRs expressed in a large spectrum of mammalian cells.
肺癌与吸烟之间存在很强的病因学关联。在两种最常见的组织学肺癌类型中，小细胞癌（SCLC）几乎仅见于吸烟者，而周围型腺癌（PAC）也在大量非吸烟者中发生。N'-亚硝基降烟碱（NNN）和4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK），即尼古丁衍生的亚硝胺，是烟草制品中含有的强力肺致癌物。由于NNN和NNK与尼古丁在结构上相似，我们推测这些致癌物是烟碱型乙酰胆碱受体（nAChRs）的配体。在受体结合和细胞增殖试验中，使用源自人小细胞肺癌和肺腺癌的细胞系以及位点选择性配体α-银环蛇毒素（α-BTX）和埃博霉素（EB），我们发现SCLC表达对α-BTX具有高亲和力的神经元烟碱型受体，而PAC细胞表达对EB具有高亲和力的烟碱型受体。NNK与SCLC细胞中对α-BTX敏感的nAChRs具有高亲和力结合，而NNN与PAC细胞中对EB敏感的nAChRs具有高亲和力结合。每种亚硝胺对这些受体的亲和力比尼古丁高几个数量级。NNK通过这种机制刺激SCLC细胞的增殖。我们的研究结果表明，NNK可能通过慢性刺激这些细胞中表达的α-BTX敏感nAChR亚型而导致吸烟者发生SCLC。这两种亚硝胺也可能导致许多目前认为由尼古丁与广泛哺乳动物细胞中表达的nAChRs慢性相互作用引起的与尼古丁相关的疾病。
