Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking: Project 5: Metabolism of NNK Among African Americans
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.
Observational Model: Cohort, Time Perspective: Prospective
Conduct a comprehensive analysis of urinary biomarkers of NNK metabolic activation and detoxification in African American and European American smokers.
We will recruit smokers to smoke specially prepared cigarettes containing [pyridine-D4]NNK, and measure deuterium-labeled NNK metabolites in the urine of these subjects. The rationale for the use of deuterium-labeled NNK is that we need to specifically identify NNK-derived metabolites, because these biomarkers are also formed as a result of nicotine metabolism. Our overall hypothesis is that 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.
Dorothy K Hatsukami, Ph.D>
University of Minnesota - Clinical and Translational Science Institute
United States: Federal Government
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