Nicotine: Potentially a Multifunctional Carcinogen?

Cigarette smoking and the use of smokeless chewing tobacco have been closely tied to the development of several human cancers, including lung, oral, esophageal, and bladder. Additionally, individuals exposed to tobacco or tobacco smoke have a substantially increased risk of cardiovascular diseases, destructive periodontitis, and pulmonary, immunological, and gastric dysfunction. Although smoking has been a major public health issue for many decades, a fairly new concern is the use of smokeless chewing tobacco, which is becoming increasingly prevalent among U.S. teenagers and young adult males. Among the most well-characterized chemicals found in tobacco and tobacco smoke are polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene, and the highly addictive alkaloid, nicotine and its metabolites. Traditionally, views of tobacco-related carcinogenesis have been centered on genotoxic mechanisms, i.e., DNA damage/mutation inflicted by the binding of bioactivated and nucleophilic components such as the PAHs. However, with the realization that cancer is a multistep process, requiring many types of chemically mediated insults, came closer scrutiny of the additional, less obviously genotoxic, chemicals present in tobacco. Nicotine, as one of the most biologically active chemicals in tobacco smoke and smokeless tobacco, has been the subject of intense scientific scrutiny. It is now known that nicotine, working through the neuronal nicotinic acetylcholine receptors (nAChRs) in the brain, is responsible for the addictive nature of tobacco use; the alkaloid has also been implicated in pathologies such as delayed wound healing and reproductive disorders. Studies on the cellular effects of nicotine have used a variety of functional endpoints in many different cell types. From this work, it has become apparent that nicotine binds to multiple receptors and activates several highly central signal transduction pathways. As a result, nicotine exerts diverse cell-type specific effects. To further complicate the picture, nicotine is converted, during the production of cigarettes and chewing tobacco, to two highly mutagenic nitrosamines, N Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK), and is metabolized in vivo to cotinine. These chemical derivatives also exhibit a wide spectrum of biological activity as compared to the parent compound. The cells of the oral cavity in smokers are intermittently exposed to very high concentrations of the component chemicals of tobacco and tobacco smoke. Due to the relevance of the oral mucosa/submucosa as one of the earliest targets and its importance in destructive periodontal conditions, previous investigators have explored the impacts of nicotine on human gingival fibroblasts (HGF) in culture. Nicotine-induced alterations have been demonstrated in such functions as production of cell surface and extracellular matrix proteins, proliferation, attachment to various surfaces, and chemotaxis; findings have been inconsistent as to whether or not these effects are more likely mediated through classical nAChRs or an alternative (unconventional) receptor. The strength of this month’s highlighted work by Argentin and Cicchetti lies in the fact that the investigators extend these previous studies and begin to address, in a carefully orchestrated manner, multiple important aspects of nicotine toxicity/carcinogenicity in this highly relevant cell type. This work, which is carried out at physiologically relevant concentrations in vitro, examines the impact of the alkaloid on cell proliferation, apoptotic cell death, DNA integrity, and cellular redox status. The careful execution of these studies allows ties to be made among the diverse actions of nicotine and begins to address important mechanistic issues in its toxicological effects. Although a great deal of work has been carried out on the mutagenicity of the common PAHs found in cigarettes, only a few studies have addressed the genotoxic nature of nicotine itself. Although tests examining point mutagenicity have generally been negative, the alkaloid has been shown in some cases to increase chromosome aberrations in exposed cells (Trivedi et al., 1990). However, findings in this regard have been somewhat inconsistent, thus highlighting the need for 1 For correspondence via fax: (970) 491-8304. E-mail: julie.campain@ colostate.edu.