Nicotine, Smoking, and Cancer

 

Nicotine is a Danger in Disguise -- Evidence supporting the link between smoking cigarettes and development of lung cancer has been in existence for decades. Much of the previous research regarding the metabolism of nicotine--the component of cigarettes that make them addictive--focused on the 5'-hydroxylation pathway. In November, 2000, Hecht et al. showed that another pathway of nicotine metabolism produces lung carcinogens. The 2'-hydroxylation pathway of nicotine directly produces intermediates that are readily modified into compounds known to cause lung cancer in lab animals. These recent findings are especially applicable to ex-smokers undergoing nicotine replacement therapy (nicotine patch, nicotine gum, etc.), since the metabolism of nicotine itself causes an elevated risk of cancer. The 2'-hydroxylation pathway further supports the fact that smoking cigarettes increases the likelihood of tumor development, not only from the vast multitude of carcinogens present in cigarette smoke, but also from nicotine itself.

Carcinogenic Precursors -- In an effort to transform nicotine metabolites into an excretable form, an organism performs a series of enzymatic alterations producing multiple metabolic intermediates. Although nicotine itself is not carcinogenic, many of the compounds that are generated by nicotine metabolism are potent carcinogens with remarkable specificity for lung tissue. One of the major metabolic products of nicotine is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK causes adenoma and adenocarcinoma of the lung regardless of the manner in which nicotine is introduced in the body. NNK will not become carcinogenic unless metabolically activated. Metabolic activation pathways compete with detoxification pathways, which attempt to protect genetic material from damage. The ratio of activation and detoxification pathways varies widely among individuals and largely dictates the risk of cancer development (Hecht 1999).

Metabolism of Nicotine Produces Harmful Products -- Nicotine metabolism has been studied for over 50 years. Most previous research has concentrated on the 5'-hydroxylation mechanism, N-oxidation, and conjugation pathways. 5'-hydroxylation is the main pathway for production of cotinine, the most prevalent nicotine metabolite. Recently, Hecht et al. (2000) investigated the 2'-hydroxylation of nicotine by cytochrome P450 2A6. This pathway was found to be the major source of NNK production from nicotine. It is the breakdown of NNK and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) that results in the formation of lung carcinogens (Hecht et al 2000). Cytochrome P450 2A6 facilitates the production of nicotine and NNK metabolites, which can form DNA adducts (Hecht 1999). A DNA adduct results when a carcinogenic metabolite is covalently bound to the purine bases guanine or adenine. The process of forming DNA adducts is known as "metabolic activation." If these adducts are corrected by DNA repair mechanisms, genetic damage will likely be avoided. However, if the adducts persist and escape repair, miscoding and subsequent mutation will occur during DNA replication. A mutation in a critical region such as an oncogene or a tumor suppressor gene will result in uncontrolled cell growth-a cancerous tumor (Hecht 1999).

Composition of Cigarettes -- Ninety five percent of the smoke inhaled by someone smoking a cigarette is composed of the gases nitrogen, oxygen, and carbon dioxide. The other five percent of inhaled smoke is particulate matter containing approximately 3500 compounds. Fifty-five substances found in cigarettes evaluated by the International Agency for Research on Cancer have been declared to exhibit "sufficient evidence for carcinogenicity" in lab animals and/or humans. One of the products of nicotine metabolism induces lung cancer in rats, mice, hamsters, and even cancer-resistant strains of mice, unlike many other compounds evaluated by the IARC. One cigarette delivers anywhere from 80-770 ng of NNK to the recipient organism. Over the lifetime of a smoker, the total NNK dose received reaches the NNK dose that produces lung tumors in rats. However, the total dose of NNK experienced by a rodent in an experimental situation is less than what a human would receive while smoking because of inherent anatomical differences and rodent avoidance reactions to smoke in experimental situations. Thus, it is reasonable to conclude that the total lifetime NNK dose received by a smoker may in fact exceed the dose that causes tumorigenesis in rodents (Hecht 1999).

 

 

 

 

 

Demographics of Smoking --There are approximately 1 billion smokers worldwide, one third of these residing in China (Hecht 1999). In the United States 23% of women and 27% of men smoke, approximately 20-30% of which will develop lung cancer as a direct result of smoking cigarettes (Scherer 1999). Lung cancer accounts for 30% of all cancers in the United States and results in more than 400,000 deaths per year. Worldwide, more than 1 million people die from lung cancer annually. Twenty-eight percent of smoking-related deaths result from lung cancer, 37% from cardiovascular disease, and 26% from other respiratory problems and/or cancers (See Chart 1, below). The carcinogens from cigarette smoking can also cause oral, pharyngeal, and esophageal cancers. In general, cigarette smoking is associated with a younger age, lower income and education levels, as well as residence in disadvantaged neighborhoods (Bergen & Caporaso 1999). Smokers can often be categorized as "Type A" personalities, characterized by impatience, competitiveness, aggressiveness, restlessness, and feeling challenge from authority. Although some generalizations can be made, human smoking behavior is extremely variable (Scherer 1999).

Chart 1: Data taken from Scherer 1999, Hecht 1999

Disease
Lung Cancer
Cardiovascular Disease
Other Respiratory Cancers/Disorders

% of Smoking-related deaths (USA)
28
37
26

Nicotine is an Addictive Drug -- Nicotine dependence is the most commonly diagnosed psychiatric problem in the United States, and is associated with depression and anxiety. Regular smokers may experience increased levels of stress and decreased levels of physical and mental arousal, as well as a greater tendency for neuroticism and impulsive behavior. Nicotine from tobacco smoke is absorbed by bodily tissues within seconds of inhalation and has an estimated half-life of 2-3 hours. Nicotine activates the dopamine reward system of the brain as an agonist for neuronal nicotine acetylcholine receptors (nAChRs). Neuronal nicotine acetylcholine receptors are found in both the central and autonomic nervous systems, and serve to regulate the release of neurotransmitters. Chronic nicotine exposure results in an increase in the number of nAChRs, as well as a reduction of nAChR turnover on the cell surface. Nicotine tolerance is a direct result of these effects. The effective concentration of nicotine in blood plasma needed for the development of tolerance is 20-50ng/mL (Bergen & Caporaso 1999). This concentration is easily reached by smoking one cigarette if the average human being is assumed to have 5000 mL of circulating blood and 2mg of nicotine are absorbed per cigarette (Hecht 1999, The Franklin Institute).

Genetic Link to Nicotine Addiction --A smoker inhales 2-3mg of nicotine while smoking, 1-2mg of which is absorbed and metabolized. This occurs via two different pathways, both under the direction of cytochrome P450 2A6 (Bergen & Caporaso 1999). The 5'-hydroxylation pathway comprises 70-80% of nicotine metabolism, producing cotinine, which is further metabolized to other products. The recently elucidated 2'-hydroxylation pathway accounts for 10-15% of nicotine metabolism, and produces NNK, which is further metabolized to NNAL and its metabolites (Hecht et al. 2000). P450 2A6 activity varies approximately 50 fold in the human population, and this variance can be traced to CYP2A6 alleles that encode metabolic enzymes specific to nicotine (Bergen & Caporaso 1999). One percent or less of European and Middle Eastern populations have deficient CYP2A6 genes, meaning that those individuals are the most protected from carcinogens derived from tobacco products and are less likely to become nicotine dependent. CYP2A6 deficiencies are found more commonly in Asian populations. Two varieties of CYP2A6 defects are known to occur: CYP2A6*2 coding for an inactive enzyme due to lack of heme incorporation; or deletion of a part or the entire CYP2A6 gene. A study by Pianezza et al. demonstrated that people with CYP2A6*2 and CYP2A6*3 alleles were less likely to become tobacco-dependent, and that smokers with these defects smoked fewer cigarettes. Furthermore, another study by Kitagawa et al. indicated that people with two CYP2A6 gene deletions had 85% less concentration of cotinine in their urine after smoking the same number of cigarettes as people with one or no defective CYP2A6 alleles (Oscarson 1999). These data suggest a link between CYP2A6 gene activation and nicotine addiction, and more research concerning this relationship continues presently.

 

Back to Main Menu
Next Page