Pharmacogenetics of Nicotine Metabolism in African-Americans
Condition: Cigarette Smoking
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators hypothesize that African Americans (AAs) smoke more for positive
      reinforcement from nicotine with a "peak-seeking" pattern of smoking (smoking individual
      cigarettes more intensively with greater intake of nicotine and tobacco smoke toxins), while
      whites smoke more for negative reinforcement with a "trough-maintaining" pattern (avoiding
      withdrawal by maintaining more consistent nicotine levels throughout the day by means of a
      more regular smoking pattern). The investigators believe that these patterns are linked to
      identifiable racial differences in nicotine pharmacology and that there will be associated
      racial differences in responses to pharmacologic interventions.
    

Detailed description: 
      Smoking is the major preventable cause of cancer, premature cardiovascular disease and
      chronic obstructive lung disease, reproductive problems and infections. AA smokers have a
      substantially higher risk of cancer and reproductive disorders compared to whites. A recently
      published large cohort study (183,000 subjects) found a two-fold higher incidence of lung
      cancer in AAs compared to whites (at cigarette consumption levels of <10 and 11-20 CPD, but
      not for >30 CPD) (1).

      Several lines of evidence indicate that AAs are more highly addicted to cigarette smoking
      than are whites. AAs are more likely to smoke their first cigarette within 10 minutes of
      awakening, an indicator of the severity of the dependence.(2) They are more likely to want to
      quit smoking and are more likely to try to quit (attempts lasting at least 24 hours),(3) but
      are significantly less likely than whites to be successful abstainers at one year. The quit
      ratio (former smokers/ever smokers) was recently reported to be 37.3% in AAs compared to 51%
      for whites.(2)

      Research suggests that AAs, who smoke fewer CPD but take in more nicotine per cigarette, are
      behaving like peak-seekers (smoking primarily for the direct nicotine-mediated positive
      reinforcement). In contrast, whites, who smoke more CPD with less nicotine intake per
      cigarette, are behaving more like trough-maintainers (seeking to maintain consistent nicotine
      levels through the day, presumably to avoid withdrawal symptoms and/or to desensitize
      receptors).

      Studies in our laboratory have shown that AAs metabolize nicotine, and to a greater extent,
      cotinine, more slowly than do whites (7,10) with slower metabolism by both the CYP2A6 and
      glucuronidation pathways. We have used the 3HC/COT ratio measured in blood or urine in
      several studies to show that CYP2A6 activity is lower in AAs compared to whites, including
      among children. More than 90 CYP2A6 gene variants have been identified. Although many are
      uncommon and their activity has not been determined (12), some are associated with large
      individual differences in the rate of nicotine metabolism (13). Studies of CYP2A6 genetics in
      AAs have only recently been reported. It is unclear whether reported gene variants in AAs can
      explain the substantial differences in nicotine and especially cotinine metabolism that we
      have observed in our prior studies. A comprehensive study of nicotine and cotinine kinetics
      and metabolism after IV dosing in relation to genotype, such as we have recently conducted in
      whites, is proposed to understand the metabolism of nicotine in AAs.
    

Intervention name(s): Deuterated nicotine and cotinine
Intervention type(s): Drug
Intervention description(s): used as a marker for pharmacokinetic studies
Intervention MeSH terms: Nicotine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Cigarette Smoking in African Americans