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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA138338-03
Application #
8375627
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$132,807
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Patel, Yesha M; Park, Sunghim L; Han, Younghun et al. (2016) Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk. Cancer Res 76:5768-5776
Park, Sungshim L; Tiirikainen, Maarit I; Patel, Yesha M et al. (2016) Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risks of lung cancer and effect on their smoking intensity. Carcinogenesis 37:269-79
Ma, Bin; Ruszczak, Chris; Jain, Vipin et al. (2016) Optimized Liquid Chromatography Nanoelectrospray-High-Resolution Tandem Mass Spectrometry Method for the Analysis of 4-Hydroxy-1-(3-pyridyl)-1-butanone-Releasing DNA Adducts in Human Oral Cells. Chem Res Toxicol 29:1849-1856
Zanetti, Krista A; Wang, Zhaoming; Aldrich, Melinda et al. (2016) Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population. Lung Cancer 98:33-42
Patel, Yesha M; Park, Sungshim L; Carmella, Steven G et al. (2016) Metabolites of the Polycyclic Aromatic Hydrocarbon Phenanthrene in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer. PLoS One 11:e0156203
Haiman, Christopher A; Patel, Yesha M; Stram, Daniel O et al. (2016) Benzene Uptake and Glutathione S-transferase T1 Status as Determinants of S-Phenylmercapturic Acid in Cigarette Smokers in the Multiethnic Cohort. PLoS One 11:e0150641
Kotapati, Srikanth; Esades, Amanda; Matter, Brock et al. (2015) High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation. Chem Biol Interact 241:23-31
Zarth, Adam T; Murphy, Sharon E; Hecht, Stephen S (2015) Benzene oxide is a substrate for glutathione S-transferases. Chem Biol Interact 242:390-5
Kotandeniya, Delshanee; Carmella, Steven G; Ming, Xun et al. (2015) Combined analysis of the tobacco metabolites cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in human urine. Anal Chem 87:1514-7
Park, Sungshim L; Carmella, Steven G; Ming, Xun et al. (2015) Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. Cancer Epidemiol Biomarkers Prev 24:561-9

Showing the most recent 10 out of 34 publications