Interindividual Differences in DNA Adduct Formation and Detoxification of 1,3-Butadiene-Derived Epoxide in Human HapMap Cell Lines

Amanda Degner, Rashi Arora, Luke Erber, Christopher Chao, Lisa A. Peterson, Natalia Y. Tretyakova

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Smoking-induced lung cancer is a major cause of cancer mortality in the US and worldwide. While 11-24% of smokers will develop lung cancer, risk varies among individuals and ethnic/racial groups. Specifically, African American and Native Hawaiian cigarette smokers are more likely to get lung cancer as compared to Caucasians, Japanese Americans, and Latinos. It is important to identify smokers who are at the greatest risk of developing lung cancer as they should be candidates for smoking cessation and chemopreventive intervention programs. Among 60+ tobacco smoke carcinogens, 1,3-butadiene (BD) is one of the most potent and abundant (20-75 μg per cigarette in mainstream smoke and 205-361 μg per cigarette in side stream smoke). BD is metabolically activated to 3,4-epoxy-1-butene (EB), which can be detoxified by glutathione S-transferase theta 1 (GSTT1)-mediated conjugation with glutathione, or can react with DNA to form 7-(1-hydroxy-3-buten-2-yl)guanine (EB-GII) adducts. In the present study, we employed EBV-transformed human lymphoblastoid cell lines (HapMap cells) with known GSTT1 genotypes to examine the influence of the GSTT1 gene on interindividual variability in butadiene metabolism, DNA adduct formation/repair, and biological outcomes (apoptosis). We found that GSTT1- HapMap cells treated with EB in culture produced lower levels of glutathione conjugates and were more susceptible to apoptosis but had similar numbers of EB-GII adducts as GSTT1+ cells. Our results suggest that GSTT1 can influence an individual's susceptibility to butadiene-derived epoxides.

Original languageEnglish (US)
Pages (from-to)1698-1708
Number of pages11
JournalChemical research in toxicology
Volume33
Issue number7
DOIs
StatePublished - Jul 20 2020

Bibliographical note

Funding Information:
This study was supported by a Program Project grant from the National Cancer Institute (5P01CA138338). NMR experiments were supported by Grant 1S10OD021536 (G. Veglia) from the National Institute of General Medical Sciences.

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