Nicotine and nitrosamines are the two opposite faces of tobacco use. The nicotine in tobacco is the reason that smoking has spread to the entire world. Nicotine is a powerful alkaloid toxin, but when taken in small doses, it is a mild stimulant. Some smokers report that it arouses alertness and enhances concentration, and for others, it is soothing and calming. This self-administered stimulation, however, is addictive. The nicotine in smoke crosses into the blood in seconds and targets the brain's reward system, stimulating the receptors that reward essential activities like eating when hungry. Smokers quickly come to crave this reward, requiring increasing amounts as the body becomes habituated, and facing powerful withdrawal symptoms when quitting. The addictive but pleasurable stimulation of nicotine, combined with an aggressive tobacco industry, has chained roughly a quarter of the U.S. population to smoking.
The rewards of nicotine, however, come with a terrible cost. Nitrosamines are the dark face of nicotine, leading directly to a high risk of cancer. Nitrosamines are nicotine-derived compounds, also found in tobacco, which are activated within the body to form powerful alkylating agents that attack DNA. Nicotine-derived nitrosaminoketone (NNK) (Fig. 1) and many similar compounds are found in tobacco products and are delivered along with nicotine to the respiratory tract in tobacco smoke.
NNK has a reactive nitrosamino group, with a methyl group on one side and a larger ketone group on the other. When activated in the body, either the methyl or the ketone group may be transferred to a DNA base. This can lead to misreading of the genetic information when the DNA is replicated. The methyl groups are particularly insidious, because they are small enough to evade the normal repair systems but different enough to corrupt the normal pairing of bases. The methyl groups from NNK commonly lead to mutations that change a guanine to an adenine, as shown in Figure 2 and Figure 3.
Nitrosoamines are not the end of the story, however. Dozens of other carcinogenic compounds have been identified in tobacco smoke that modify and mutate DNA in other ways. Smokers are constantly attacking the DNA in their cells, making changes randomly in multiple genes. In one out of five smokers, these mutations will build up over the years and ultimately corrupt just the right combination of genes, creating a cancer cell.