Chapter 11 - Nitrosamines derived from nicotine and other tobacco alkaloids

Abstract

While nicotine is not a carcinogen, several tobacco-specific nitrosamines derived from nicotine and other tobacco alkaloids are carcinogenic in laboratory animals; a property characteristic of over 200 nitrosamines 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK), 4-(methylnitrosamino)-l-(3-pyridyl)- 1-butanol (NNAL), and N'-nitrosonornicotine (NNN) are strong rodent carcinogens, while N'-Nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), iso-NNAL, and 4-(methylnitrosamino)- l-(3-pyridyl)butyric acid (iso-NNAC) have little or no activity. The carcinogenicity of NNK, NNAL, and NNN leads to the hypothesis that they may play an important role in human cancer. In support of this hypothesis, numerous analytical studies summarized the presence of tobacco-specific nitrosamines in cured, unburned tobacco, as well as in tobacco smoke. Virtually, all marketed tobacco products contain these compounds. Numerous studies in rodents and primates, both in vitro and in vivo, demonstrate that NNK, NNAL, and NNN are extensively metabolized and form electrophilic intermediates that form covalent adducts with DNA and hemoglobin. These studies provide the mechanistic foundation for understanding the carcinogenic activities of tobacco-specific nitrosamines. The results of the carcinogenicity studies of NNK, NNAL, and NNN further support the hypothesis that these nitrosamines may be important in tobacco induced cancer. The structural similarities of NNK, NNAL, and NNN to nicotine indicate that these nitrosamines, like nicotine, should be extensively metabolized in humans; this has been difficult to demonstrate so far, due in part to the identical structures of nicotine and tobacco-specific nitrosamine metabolites.