Butadiene is an important tobacco smoke carcinogen likely to be involved in the induction of lung tumors in smokers. Butadiene is classified as a known human carcinogen based on epidemiological evidence indicating increased cancer incidence in occupationally exposed workers and in inhalation studies in laboratory animals. The recognized critical step in butadiene-mediated carcinogenesis is the chemical modification of DNA by the epoxy metabolites of butadiene to form covalent adducts. Previous studies have shown that genetic variations in metabolism and repair genes can mediate the sensitivity to butadieneinduced mutations and cancer. Because ofthe requirement for metabolic activation of butadiene, enzymes that are involved in the formation and detoxification of butadiene epoxides largely determine the individual sensitivity to butadiene-mediated mutagenesis and carcinogenesis. Many prominent polymorphisms in genes coding for butadiene metabolizing enzymes, e.g. CYP2E1, EPHX1. and GSTT1, have been identified. Because their frequency differs between ethnic/racial groups, these genetic changes may contribute to the observed inter-ethnic/inter-racial differences in the incidence of lung cancer. Future studies are warranted to determine how the expression levels and genetic variations in biotransformation genes influence the metabolism and biological effects of butadiene in humans. We hypothesize that human populations of different ethnicity/race metabolize butadiene differentiy, contributing to differing degrees of cancer risk following exposure to butadiene in tobacco smoke. The obiective of this application is to investigate inter-individual and inter-ethnic/racial differences in the metabolism of butadiene and in the formation of butadiene-induced DNA adducts and to link these differences to specific polymorphisms of carcinogen metabolism and DNA repair genes. Studies proposed here will quantify the major urinary metabolites of butadiene and butadiene-induced DNA adducts in smokers of varying ethnic groups and identify the effects of genetic polymorphisms on the genotoxicity of butadienederived epoxides. Our approach is innovative, because we will, for the flrst time, analyze the effects of ethnicity/race on butadiene metabolism and DNA adduct formation in a large multi-ethnic cohort.

Public Health Relevance

Although smoking is a recognized risk factor for lung cancer, one out of five Americans continue to smoke. About 15% of smokers will develop lung cancer over the lifetime, with a greater cancer incidence in African American and Native Hawaiian cigarette smokers as compared with European Americans, Japanese Americans, and Latinos. Our studies will help provide insight into the origins of this variability in sensitivity to smoking-mediated lung cancer and help identify individuals at risk who should be candidates for special smoking cessation intervention or chemopreventive therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
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
Murphy, Sharon E; Park, Sungshim Lani; Balbo, Silvia et al. (2018) Tobacco biomarkers and genetic/epigenetic analysis to investigate ethnic/racial differences in lung cancer risk among smokers. NPJ Precis Oncol 2:17
Murphy, Sharon E; von Weymarn, Linda B; Parenteau, Marc et al. (2018) Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N-glucuronide by African American Smokers. Chem Res Toxicol 31:168-175
Degner, Amanda; Carlsson, Henrik; Karlsson, Isabella et al. (2018) Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood. Chem Res Toxicol :
Chai, Weiwen; Morimoto, Yukiko; Cooney, Robert V et al. (2017) Dietary Red and Processed Meat Intake and Markers of Adiposity and Inflammation: The Multiethnic Cohort Study. J Am Coll Nutr 36:378-385
Park, Sungshim L; Murphy, Sharon E; Wilkens, Lynne R et al. (2017) Association of CYP2A6 activity with lung cancer incidence in smokers: The multiethnic cohort study. PLoS One 12:e0178435
Murphy, Sharon E (2017) Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chem Res Toxicol 30:410-419
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
Sangaraju, Dewakar; Boldry, Emily J; Patel, Yesha M et al. (2017) Isotope Dilution nanoLC/ESI+-HRMS3 Quantitation of Urinary N7-(1-Hydroxy-3-buten-2-yl) Guanine Adducts in Humans and Their Use as Biomarkers of Exposure to 1,3-Butadiene. Chem Res Toxicol 30:678-688
Peterson, Lisa A (2017) Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK. Chem Res Toxicol 30:420-433

Showing the most recent 10 out of 44 publications