Pharmacogenetics of Nicotine Metabolism in African-Americans

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.