This research will investigate genetic and dietary influences on the Phase I metabolism of tobacco smoke carcinogens and on lung cancer risk. Based on recent findings, we hypothesize that, in smokers: 1) polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke are the primary cause of squamous cell carcinoma of the lung, whereas nitrosamines in tobacco are the primary cause of lung adenocarcinoma; 2) the metabolic activation of PAHs is mainly carried out by CYPIA1, with more minor roles for CYP3A4 and CYP1B 1, and the activation of tobacco-specific nitrosamines (TSNAs) is mainly carried out by CYP2E1, CYPlA2 and CYP2A6; and 3) the activation of these carcinogens is modified by polymorphic genes and dietary inhibitors/inducers. We will use genomic DNA samples from a completed case-control study of lung cancer among Japanese, Caucasians and Hawaiians (341 cases, 456 controls) to test the independent and joint associations of these polymorphisms with lung cancer risk. We will also conduct a cross-sectional study (n=600) among Japanese, Hawaiian and Caucasian smokers participating in our Multiethnic Cohort Study to test associations of: 1) urinary NNAL (the main metabolite of NNK) and TSNA globin adducts with the high activity genotypes for CYP2E1, CYIA2 and/or CYP2A6; 2) urinary total 1-hydroxypyrene and levels of PAH DNA adducts in circulating lymphocytes with the high activity genotypes for CYPIAI, AhR and CYPIBI; and 3) intake and urinary levels of phytochemicals (specific flavonoids, total isothiocyanates) and plasma levels of micronutrients with these markers of activation. Finally, two feeding studies (n=50 each) will use a randomized cross-over design to test the effect of selected foods on markers of PAH or TSNA metabolism and on metabolizing enzymes in smokers with high and low activity genotypes. The elucidation of the main enzymes responsible for carcinogen activation and of the impact of dietary factors on these enzymes would have important implications for cancer prevention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Starks, Vaurice
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Hawaii
Organized Research Units
United States
Zip Code
Park, Sungshim L; Patel, Yesha M; Loo, Lenora W M et al. (2018) Association of internal smoking dose with blood DNA methylation in three racial/ethnic populations. Clin Epigenetics 10:110
Boldry, Emily J; Patel, Yesha M; Kotapati, Srikanth et al. (2017) Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer. Cancer Epidemiol Biomarkers Prev 26:1034-1042
Park, Sungshim Lani; Kotapati, Srikanth; Wilkens, Lynne R et al. (2014) 1,3-Butadiene exposure and metabolism among Japanese American, Native Hawaiian, and White smokers. Cancer Epidemiol Biomarkers Prev 23:2240-9
Truong, Therese; Hung, Rayjean J; Amos, Christopher I et al. (2010) Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 102:959-71
Derby, Kiersten S; Cuthrell, Kristine; Caberto, Christian et al. (2009) Exposure to the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokers from 3 populations with different risks of lung cancer. Int J Cancer 125:2418-24
Derby, Kiersten S; Cuthrell, Kristine; Caberto, Christian et al. (2008) Nicotine metabolism in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiol Biomarkers Prev 17:3526-35
Le Marchand, Loic; Derby, Kiersten S; Murphy, Sharon E et al. (2008) Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res 68:9137-40
Le Marchand, Loic; Wilkens, Lynne R (2008) Design considerations for genomic association studies: importance of gene-environment interactions. Cancer Epidemiol Biomarkers Prev 17:263-7
Le Marchand, Loic; Guo, Chuanfa; Benhamou, Simone et al. (2003) Pooled analysis of the CYP1A1 exon 7 polymorphism and lung cancer (United States). Cancer Causes Control 14:339-46
Le Marchand, Loic; Donlon, Timothy; Lum-Jones, Annette et al. (2002) Association of the hOGG1 Ser326Cys polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev 11:409-12

Showing the most recent 10 out of 12 publications