title: Novel adducts from the reaction of 1-chloro-3-buten-2-one with 2'-deoxyguanosine. Structural characterization and potential as tools to investigate 1,3-butadiene carcinogenicity.
abstract: 1-Chloro-3-buten-2-one (CBO) is a potential reactive metabolite of 1,3-butadiene (BD), a carcinogenic air pollutant. To develop tools that may help investigate the role of CBO in BD carcinogenicity and to develop biomarkers that can be used to assess BD exposure, the reaction of CBO with 2'-deoxyguanosine (dG) under in vitro physiological conditions (pH 7.4, 37°C) was investigated and the products (designated as CG-1, CG-2, CG-3, CG-4, CG-5, and CG-6 based on their retention times on HPLC) were characterized by MS and NMR spectroscopy. The structures of CG-1, CG-2, CG-3, and CG-4 were 1,N2-(3-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyguanosine, N7-(4-chloro-3-oxobutyl)-2'-deoxyguanosine, N7,8-(3-hydroxy-3-chloromethylpropan-1,3-diyl)guanine and N2-(4-chloro-3-oxobutyl)-2'-deoxyguanosine, respectively. CG-5 and CG-6, a pair of diastereomers, were characterized as 1,N2-(3-hydroxy-3-chloromethylpropan-1,3-diyl)-2'-deoxyguanosine. CG-1 was stable under in vitro physiological conditions, whereas CG-2, CG-3, CG-4, and CG-5/6 were unstable and exhibited the half-lives at <1.0, 4.8±0.1, 6.7±0.3, and 2.7±0.1 h, respectively. CG-2 decomposed primarily via a retro-Michael reaction to produce dG and CBO, with only a small fraction of CG-2 degrading to CG-3. Decomposition of CG-4 proceeded via a cyclization reaction and/or replacement of the chlorine atom by a hydroxyl group to form 1,N2-(1-hydroxy-1-hydroxymethylpropan-1,3-diyl)-2'-deoxyguanosine (CG-4D1) and N(2)-(4-hydroxy-3-oxobutyl)-2'-deoxyguanosine (CG-4D2), whereas decomposition of CG-5/6 yielded CG-1. Collectively, the newly characterized CBO adducts could be used to investigate the role of CBO in the mechanism of BD carcinogenicity and could also be used to develop biomarkers for BD exposure.
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Ying-Xin
authors.initials: YX
authors.lastname: Yu
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China. Electronic address: xyzhang999@shu.edu.cn.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Department of Comparative Biosciences and the Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI 53706, United States. Electronic address: elfarra@svm.vetmed.wisc.edu.
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Elfarra
mesh_terms: D002074:Butanones / Q000737:chemistry* / Q000633:toxicity*; D002273:Carcinogens / Q000737:chemistry* / Q000633:toxicity*; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics
chemical_list: C580717:1-chloro-3-buten-2-one; D002074:Butanones; D002273:Carcinogens; D018736:DNA Adducts; D003849:Deoxyguanosine
keywords: 1,3-Butadiene; 1-Chloro-3-buten-2-one; 2′-Deoxyguanosine; Bioactivation; Biomarkers; DNA adducts