Genetic determinants of 1,3-butadiene metabolism and detoxification in three populations of smokers with different risks of lung cancer

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) and Nacetyl-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 1025). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected by GSTT1 gene copy number (P < 0.0001); conditional on GSTT1, no other polymorphisms showed a significant association. Urinary DHBMA levels also differed between ethnic groups (P 3.3 104), but were not affected by GSTT1 copy number (P 0.226). Conclusions: GSTT1 gene deletion has a strong effect on urinaryMHBMAlevels, and thereforeBDmetabolism, 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 by GSTT1 genotype.