Metabolism of NNK Among African Americans
Metabolism of NNK Among African Americans
Metabolism and DNA adduct formation are critical in cancer induction by NNK. The
 investigators goal is to understand whether the observed ethnic/racial differences in lung
 cancer incidence are due to variations in NNK metabolism. The investigators overall
 hypothesis is that cancer susceptibility relates to carcinogen dose and to the balance
 between carcinogen metabolic activation and detoxification. The investigators propose to test
 this hypothesis via investigation of potential differences in NNK metabolic activation and
 detoxification in African American and European American smokers.
Lung cancer is the most common cause of cancer death in the United States, with the annual
 number of cases estimated at 162,460 deaths per year. It is more prevalent in African
 Americans as compared to European Americans. Cigarette smoking causes up to 90% of lung
 cancer, being the major risk factor in both African Americans and European Americans.

 Tobacco-specific nitrosamines (TSNA) are among the most significant carcinogens in tobacco
 products. Multiple international studies clearly document the occurrence of substantial
 amounts of these carcinogens in both unburned tobacco and tobacco smoke. One of the most
 prevalent of these compounds, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is
 present in both unburned tobacco and cigarette smoke, and is a remarkably effective lung
 carcinogen in laboratory animals, inducing lung tumors in rodents independent of the route of
 administration. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK, is
 also a pulmonary carcinogen. NNK has been classified by the International Agency for Research
 on Cancer as a Group 1 carcinogen (carcinogenic to humans). Consistent with this, 2 recent
 studies by our group have demonstrated that levels of NNAL in serum or urine are related to
 lung cancer in smokers.

 Our primary aim is to conduct a comprehensive analysis of urinary biomarkers of NNK metabolic
 activation and detoxification in African American and European American smokers. We
 hypothesize that, after adjustment for smoking level, the relative contribution of the
 biomarkers of NNK metabolic activation to the total amount of NNK metabolites will be higher
 in African Americans as compared to European Americans. Our secondary aim is to measure in
 exfoliated oral mucosa cells of African American and European American smokers DNA adducts
 formed as a result of NNK metabolic activation. The results of these measurements will offer
 a direct measure of NNK-induced DNA damage in smokers, and will be critical to an
 understanding of the balance between the urinary excretion of NNK metabolites and the extent
 of NNK DNA binding. We hypothesize that African Americans will have in the DNA of their oral
 mucosa cells higher levels of NNK-derived DNA adducts as compared to European Americans.
 Finally, we will investigate the relationship between levels of NNK-derived DNA adducts
 measured in oral mucosa cells and the rates of repair of these adducts in cultured
 lymphocytes from our subjects. These measurements will allow us to evaluate more fully the
 role of variations in NNK metabolism in the observed differences in lung cancer risk between
 European American and African American smokers. We expect that that African Americans will
 have lower capacity to repair NNK-induced DNA damage as compared to European Americans, and
 this will correlate with higher levels of NNK-derived buccal DNA adducts.
Inclusion Criteria:

 1. Male or female subjects with a smoking history of at least 10 cigarettes daily for at
 least 1 year;

 2. Subjects report themselves, biological parents and both sets of biological
 grandparents as

 -  African American or African descent or

 -  European American or European descent

 3. Subjects are in apparently good physical health (no unstable medical condition)

 4. Subjects are in stable, good mental health (e.g. not currently, within the past 6
 months, experiencing unstable or untreated psychiatric diagnosis, including substance
 abuse, as determined by the PRIME-MD);

 5. Subjects have provided written informed consent to participate in the study.

 Exclusion Criteria:

 1. Unstable medical conditions including cancer, coronary heart disease and arrhythmia

 2. Cannot or unwilling to identify ethnic/racial ancestry

 3. Women who are currently pregnant or breast feeding

 4. Currently using any other tobacco or nicotine-containing product

 5. Currently taking any medications that affect relevant metabolic enzymes.