title: Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer.
abstract: Background:1,3-Butadiene (BD) is an important carcinogen in tobacco smoke that undergoes metabolic activation to DNA-reactive epoxides. These species can be detoxified via glutathione conjugation and excreted in urine as the corresponding N-acetylcysteine conjugates. We hypothesize that single nucleotide polymorphisms (SNPs) in BD-metabolizing genes may change the balance of BD bioactivation and detoxification in White, Japanese American, and African American smokers, potentially contributing to ethnic differences in lung cancer risk.Methods:We measured the levels of BD metabolites, 1- and 2-(N-acetyl-L-cysteine-S-yl)-1-hydroxybut-3-ene (MHBMA) andN-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA), in urine samples from a total of 1,072 White, Japanese American, and African American smokers and adjusted these values for body mass index, age, batch, and total nicotine equivalents. We also conducted a genome-wide association study to identify genetic determinants of BD metabolism.Results:We found that mean urinary MHBMA concentrations differed significantly by ethnicity (P= 4.0 × 10-25). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected byGSTT1gene copy number (P< 0.0001); conditional onGSTT1, no other polymorphisms showed a significant association. Urinary DHBMA levels also differed between ethnic groups (P= 3.3 × 10-4), but were not affected byGSTT1copy number (P= 0.226).Conclusions:GSTT1gene deletion has a strong effect on urinary MHBMA levels, and therefore BD metabolism, in smokers.Impact:Our results show that the order of MHBMA levels among ethnic groups is consistent with their respective lung cancer risk and can be partially explained byGSTT1genotype.Cancer Epidemiol Biomarkers Prev; 26(7); 1034-42. ©2017 AACR.
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Boldry
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yesha M
authors.initials: YM
authors.lastname: Patel
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Kotapati
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Amanda
authors.initials: A
authors.lastname: Esades
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Sungshim L
authors.initials: SL
authors.lastname: Park
authors.affiliation: University of Hawaii Cancer Center, Epidemiology Program, Honolulu, Hawaii.
authors.forename: Maarit
authors.initials: M
authors.lastname: Tiirikainen
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. trety001@umn.edu loic@cc.hawaii.edu daniel.stram@med.usc.edu.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: University of Hawaii Cancer Center, Epidemiology Program, Honolulu, Hawaii. trety001@umn.edu loic@cc.hawaii.edu daniel.stram@med.usc.edu.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. trety001@umn.edu loic@cc.hawaii.edu daniel.stram@med.usc.edu.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D001741:Black or African American / Q000706:statistics & numerical data; D000368:Aged; D001213:Asian / Q000706:statistics & numerical data; D015415:Biomarkers / Q000652:urine; D002070:Butadienes / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000074285:Smokers / Q000706:statistics & numerical data*; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism* / Q000652:urine; D044465:White People / Q000706:statistics & numerical data
chemical_list: C576990:1-hydroxybutene-2-yl mercapturic acid; D015415:Biomarkers; D002070:Butadienes; D002273:Carcinogens; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D005978:Glutathione; C031763:1,3-butadiene; D000111:Acetylcysteine