4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is metabolized to enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), found in the urine of virtually all people exposed to tobacco products. We assessed the carcinogenicity in male F-344 rats of (R)-NNAL (5 ppm in drinking water), (S)-NNAL (5 ppm), NNK (5 ppm) and racemic NNAL (10 ppm) and analyzed DNA adduct formation in lung and pancreas of these rats after 10, 30, 50 and 70 weeks of treatment. All test compounds induced a high incidence of lung tumors, both adenomas and carcinomas. NNK and racemic NNAL were most potent; (R)-NNAL and (S)-NNAL had equivalent activity. Metastasis was observed from primary pulmonary carcinomas to the pancreas, particularly in the racemic NNAL group. DNA adducts analyzed were O (2)-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O (2)-POB-dThd), 7-[4-(3-pyridyl)-4-oxobut-1-yl]guanine(7-POB-Gua),O (6)-[4-(3-pyridyl)-4-oxobut-1-yl]deoxyguanosine(O (6)-POB-dGuo),the 4-(3-pyridyl)-4-hydroxybut-1-yl(PHB)adductsO (2)-PHB-dThd and 7-PHB-Gua, O (6)-methylguanine (O (6)-Me-Gua) and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts. Adduct levels significantly decreased with time in the lungs of rats treated with NNK. Pulmonary POB-DNA adducts and O (6)-Me-Gua were similar in rats treated with NNK and (S)-NNAL; both were significantly greater than in the (R)-NNAL rats. In contrast, pulmonary PHB-DNA adduct levels were greatest in the rats treated with (R)-NNAL. Total pulmonary DNA adduct levels were similar in (S)-NNAL and (R)-NNAL rats. Similar trends were observed for DNA adducts in the pancreas, but adduct levels were significantly lower than in the lung. The results of this study clearly demonstrate the potent pulmonary carcinogenicity of both enantiomers of NNAL in rats and provide important new information regarding DNA damage by these compounds in lung and pancreas.
Currently, smokeless tobacco products are being proposed as an alternative mode of tobacco use associated with less harm. All of these products contain the tobacco-specific carcinogen N'-nitrosonornicotine (NNN). The major form of NNN in tobacco products is (S)-NNN, shown in this study to induce a total of 89 benign and malignant oral cavity tumors in a group of 20 male F-344 rats treated chronically with 14 p.p.m. in the drinking water. The opposite enantiomer (R)-NNN was weakly active, but synergistically enhanced the carcinogenicity of (S)-NNN. Thus, (S)-NNN is identified for the first time as a strong oral cavity carcinogen in smokeless tobacco products and should be significantly reduced or removed from these products without delay in order to prevent debilitating and deadly oral cavity cancer in people who use them.
Smokeless tobacco products, consisting most commonly of moist snuff placed in the mouth, either directly or in sachets, are gaining popularity in the U.S. In 2009, 7.0% of men and 11.0% of male high school students were current users. While smokeless tobacco use is unquestionably less harmful than cigarette smoking, it is nevertheless a recognized cause of oral cancer. A quantitatively important carcinogen in all smokeless tobacco products is N′-nitrosonornicotine (NNN), occurring at levels ranging from 0.4 - 17 µg/g dry weight in current products consumed in the U.S. These amounts are far higher than those of nitrosamines in other consumer products. NNN has a chiral center at its 2′-position and consequently exists as enantiomers. The major enantiomer in tobacco products is (S)-NNN. Racemic NNN, administered to F-344 rats in the drinking water, is known to induce tumors of the esophagus in rats, but there are no reports in the literature on the carcinogenicity of (S)-NNN. Based on DNA binding studies of (S)-NNN that demonstrated relatively high adduct levels in both the rat esophagus and oral cavity, we initiated a carcinogenicity study. Groups of 24 male F-344 rats, 7 weeks of age, were treated with (S)-NNN or (R)-NNN (15 ppm in the drinking water) or racemic NNN (15 rats, 30 ppm), or were given tap water. All rats in the groups treated with (S)-NNN or racemic NNN began losing weight after one year of treatment and had died or were euthanized for humane reasons by 17 months of treatment, while the rats given (R)-NNN and the controls were terminated at 20 months. Tumors were counted blinded to treatment. Necropsy of 20 (S)-NNN treated rats demonstrated a 100% incidence of oral tumors and a total of 91 oral tumors, including tumors of the tongue (1.5 tumors per rat), buccal mucosa (1.0), soft palate (0.5), and pharynx (0.75) in addition to esophageal tumors in all rats (6.1 tumors per rat). Some of the oral tumors were >4 mm in size: tongue (9 tumors); buccal mucosa (2); soft palate (4); pharynx (5). (R)-NNN induced oral tumors in only 5 of 24 rats and esophageal tumors in 3, while racemic NNN was also highly active causing 153 esophageal tumors and 96 oral tumors in 12 necropsied rats. Preliminary histopathological analysis of the tumors indicated that they encompass a spectrum from benign squamous papillomas to malignant squamous cell carcinomas. These results clearly demonstrate, for the first time, the strong carcinogenicity of (S)-NNN in the rat oral cavity. Thus, (S)-NNN is the only potent oral carcinogen identified in smokeless tobacco. There is an urgent need to eliminate this powerful carcinogen from tobacco products.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-63. doi:1538-7445.AM2012-LB-63
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