Metabolism of NNK Among African Americans

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking: Project 5: Metabolism of NNK Among African Americans

Conditions
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Lung Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects with a smoking history of at least 10 cigarettes daily for at least 1 year; Subjects report themselves, biological parents and both sets of biological grandparents as African American or African descent or European American or European descent Subjects are in apparently good physical health (no unstable medical condition) 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); Subjects have provided written informed consent to participate in the study. Exclusion Criteria: Unstable medical conditions including cancer, coronary heart disease and arrhythmia Cannot or unwilling to identify ethnic/racial ancestry Women who are currently pregnant or breast feeding Currently using any other tobacco or nicotine-containing product Currently taking any medications that affect relevant metabolic enzymes.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| African Americans<br>Subjects will be classified as African American if they report themselves, biological parents and both sets of biological grandparents as African American or African descent. | |
| European American<br>Subjects will be classified as European American if they report themselves, biological parents and both sets of biological grandparents as European American or European descent. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure in exfoliated oral mucosa cells of African American and European American smokers DNA adducts formed as a result of NNK metabolic activation. | We will collect exfoliated oral mucosa cell samples from the recruited subjects. DNA isolated from these samples will be analyzed for [pyridine-D4]NNK-derived adducts. Our overall hypothesis in this Specific Aim is 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. | 10 days | 
| Assess the repair of NNK-induced DNA damage. | We will investigate the relationship between the levels of NNK-derived DNA adducts measured in the oral mucosa cells and the rates of repair of these adducts in cultured lymphocytes from our subjects. Our overall hypothesis for this Specific Aim is 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 [pyridine-D4]NNK-derived buccal DNA adducts. | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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smoking, lung cancer, ethnic racial differences, tobacco specific nitrosamines, metabolism of carcinogens