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Tobacco-Specific Carcinogenic Nitrosamines: Ligands for Nicotinic Acetylcholine Receptors in Human Lung Cancer Cells
Biochemical Pharmacology (1998)
  • Hildegard M. Schuller, University of Tennessee, Knoxville
  • Michael Orloff, University of Tennessee - Knoxville
Abstract

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 α-bungarotoxin (α-BTX) and epibatidine (EB) in receptor binding and cell proliferation assays, we found that SCLC expressed neuronal nicotinic receptors with high affinity to α-BTX, whereas PAC cells expressed nicotinic receptors with high affinity to EB. NNK bound with high affinity to α-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 α-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. DOI: 10.1016/S0006-2952(97)00651-5

Keywords
  • tobacco-specific,
  • nitrosamine,
  • nicotinic receptor,
  • α-bungarotoxin,
  • epibatidine
Publication Date
May 1, 1998
Citation Information
Hildegard M. Schuller and Michael Orloff. "Tobacco-Specific Carcinogenic Nitrosamines: Ligands for Nicotinic Acetylcholine Receptors in Human Lung Cancer Cells" Biochemical Pharmacology Vol. 55 Iss. 9 (1998)
Available at: http://works.bepress.com/hildegard_schuller/32/