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National Research Forum on Nicotine Addiction - smoke spacer

Addicted to Nicotine
A National Research Forum

Section II: Nicotine-Individual Risk Factors for Initiation
Richard R. Clayton, Ph.D., Chair


Karen Ahijevych, Ph.D., R.N.
College of Nursing
Ohio State University


Nicotine metabolism might be relevant to nicotine addiction since metabolism influences a person's exposure to the psychoactive substance nicotine. Individual variation in nicotine metabolism may play a role in a person's level of smoking, as well as the transition from initiation to maintenance of a smoking behavior pattern. Slower nicotine metabolism permits longer exposure to nicotine and therefore may yield fewer cigarettes smoked per day. Slower metabolism in naive smokers may potentially reduce the likelihood of their becoming regular smokers, which is related to more aversive symptoms from nicotine exposure. Persons with faster nicotine metabolism may smoke more cigarettes per day to maintain nicotine levels and be more likely to develop and maintain a smoking pattern. While there are numerous factors that affect initiation of smoking behavior, nicotine metabolism could be one important aspect. Since there is a paucity of research on nicotine metabolism in youth, a brief review of salient aspects of nicotine metabolism in adults provides a basis from which to extrapolate.

What We Know

Nicotine metabolism is complex. Nicotine, a highly lipid-soluble alkaloid, is converted to cotinine in a two-step process involving cytochrome P450 and aldehyde oxidase. Nicotine is eliminated primarily by hepatic metabolism by way of C-oxidation to cotinine, the major metabolite. While nicotine has a relatively short half-life of about 2 hours, cotinine has a half-life of approximately 20 hours. Therefore, cotinine provides a more stable marker of exposure in the person since there is less variability in cotinine throughout the day than that observed for nicotine.

Possible explanations for different levels of the metabolite cotinine in persons who have similar smoking rates include differences in nicotine absorption and distribution, differences in the depth and duration of inhalation during smoking, differences in swallowed, nicotine-laden saliva, the effect of mentholated cigarettes on smoke constituent exposure, genetic differences in nicotine metabolism, and differences in cotinine elimination. Variables affecting the biotransformation of nicotine have been identified. Several studies indicate that male smokers may metabolize nicotine faster than female smokers. Daily activities, such as consuming a meal, increase nicotine metabolism. An average 42 percent increase in nicotine clearance approximately 1 hour after beginning the meal may be related to increases in liver blood flow with the meal. Smokers typically smoke after meals, and decreased plasma nicotine caused by increased nicotine clearance with increased hepatic blood flow could contribute to the urge to smoke.

To illustrate differences in individual metabolism variability in the natural environment, several studies have identified higher cotinine levels in African-American compared with Caucasian smokers, resulting in lower smoking rates among African Americans. In a two-factor study of menthol preference and ethnicity, African-American women smoked significantly fewer cigarettes per day than did Caucasian women, and yet their average cotinine level was significantly higher. There were no differences by ethnicity on smoking topography measures except for a longer exhalation duration time in Caucasian women. There were significant effects of mentholated cigarettes across ethnic groups since half of each group preferred nonmenthol cigarettes based on stratified recruitment. Menthol smokers had larger puff volumes, higher cotinine levels, and shorter time to first cigarette. Menthol cigarettes are the predominant choice of African-American smokers and thus have implications for clinicians working with African-American youth exposed to this type of cigarette, with its higher tar and nicotine content.

Higher levels of cotinine in African-American smokers compared with Caucasians may also be related to the findings of a recent study of nicotine and cotinine clearance in African-American and Caucasian smokers assessed with dual-labeled nicotine and cotinine infusions. While clearance of nicotine was similar for African Americans and Caucasians, the clearance of cotinine was significantly slower in African Americans.

Genetic variability in nicotine metabolism is another important factor in understanding interindividual differences of consumption and exposure. In vitro studies have identified several different cytochrome P450 isozymes in the C-oxidation of nicotine. CYP2A6 and CYP2D6 have displayed genetic polymorphisms suggesting that individuals who lack these enzymes may be poor metabolizers of nicotine. It was recently reported that 60 to 80 percent of nicotine is metabolized to cotinine by CYP2A6, which is polymorphically expressed as the wild-type and two null alleles CYP2A6*2 and *3. Cotinine formation in human liver microsomes was significantly correlated with CYP2A6 levels leading to the conclusion that CYP2A6 is the principal cytochrome P450 involved in nicotine metabolism. Variation in CYP2A6 was identified as the major reason for interindividual differences in nicotine kinetics in human liver microsomes. In other work, smokers homozygous for wild-type active CYP2A6 alleles smoked significantly more cigarettes per day than heterozygous smokers (carriers of one defective CYP2A6 allele). A significantly lower prevalence of CYP2A6 v1, the variant allele that encoded an inactive enzyme, was identified among African Americans (0 percent) versus English Caucasians (17 percent). In another sample, the prevalence of two variant alleles of CYP2A6 was 2.6 and 6.6 percent in Caucasians and .9 and 13.9 percent in Canadian Native Americans. While earlier studies had examined the potential role of CYP2D6 in nicotine metabolism, a recent study reported that CPY2D6 was not important in nicotine metabolism in human liver microsomes. In addition, CYP2A6 has been shown to metabolically activate procarcinogens such as aflatoxin B1 and N-nitrosodiethylamine; thus, the polymorphism of CYP2A6 is important as a factor of cancer susceptibility.

Smoking initiation is multifactorial, with nicotine metabolism being only one factor. Extrapolating what we know about adults, we can postulate that there is variability in nicotine metabolism among youth related to differences in nicotine absorption and distribution, differences in the depth and duration of inhalation during smoking, the effect of mentholated cigarettes on smoke constituent exposure, genetic differences in nicotine metabolism, and differences in cotinine elimination. Plasma nicotine half-life in "chippers" (persons who smoke fewer cigarettes intermittently) was similar to the nicotine half-life in regular smokers. This provides information about nicotine levels in persons with smoking patterns that may resemble youth in smoking initiation. The chippers' lower smoking rate did not yield increased nicotine levels as a result of diminished nicotine disposition or clearance. A small study of adolescent smokers reported lower blood cotinine levels than those in adults with comparable smoking rates. However, investigators postulated overreporting of smoking rate by adolescents as one explanation for the differences. Other biological measures of smoke constituent exposure in youth in initiation phases are lacking.

Individual differences in sensitivity to nicotine address the range of response to a specified drug dose. Sensitivity has been described in relation to the initial experiences with smoking and individuals subsequently becoming smokers or nonsmokers. Smokers classified as "more dependent" recalled significantly more pleasurable sensations with initial smoking experiences than less dependent smokers. The ratio of pleasurable to unpleasant sensations was significantly higher in more dependent versus less dependent smokers. It was proposed that those who become smokers are more sensitive to the reinforcing properties of nicotine and are undeterred by the negative effects. In addition, examination of first-dose sensitivity to nicotine in mice indicated that those more reactive initially developed greater tolerance and were more willing to self-administer.

What We Need To Know More About

  • Characterization of nicotine metabolism in adolescents in the experimentation phase of smoking initiation.

  • Examination of differences in nicotine metabolism and susceptibility to nicotine addiction in adolescents.

  • Description of smoking topography and nicotine metabolism in adolescents from multiple ethnic groups in the smoking initiation phase.

  • Examination of nicotine sensitivity in the smoking initiation phase.

  • Assessment of the prevalence of CYP2A6 variant alleles in the initiation phase and their relationship to the transition to becoming a regular smoker.

Recommended Reading

Fernandez-Salguero, P.; Hoffman, S.M.; Cholerton, S.; Mohrenweiser, H.; Raunio, H.; Rautio, A.; Pelkonen, O.; Huang, J.D.; Evans, W.E.; Idle, J.R.; et al. A genetic polymorphism in coumarin 7-hydroxylation: Sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet 57:651-660, 1995.

Messina, E.S.; Tyndale, R.F.; and Sellers, E.M. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 282:1608-1614, 1997.

Pomerleau O.F. Individual differences in sensitivity to nicotine: Implications for genetic research on nicotine dependence. Behav Genet 25:161-177, 1995.

Nakajima, M.; Yamamoto, T.; Nunoya, K.; Yokoi, T.; Nagashima, K.; Inoue, K.; Funae, Y.; Shimada, N.; Kamataki, T.; and Kuroiwa, Y. Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos 24:1212-1217, 1996.

Seaton, M., and Vesell, E. Variables affecting nicotine metabolism. Pharmacol Ther 60:461-500, 1993.

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