title: Formation of fused-ring 2'-deoxycytidine adducts from 1-chloro-3-buten-2-one, an in vitro 1,3-butadiene metabolite, under in vitro physiological conditions.
abstract: 1-Chloro-3-buten-2-one (CBO) is a potential metabolite of 1,3-butadiene (BD), a carcinogenic air pollutant. CBO is a bifunctional alkylating agent that readily reacts with glutathione (GSH) to form mono-GSH and di-GSH adducts. Recently, CBO and its precursor 1-chloro-2-hydroxy-3-butene (CHB) were found to be cytotoxic and genotoxic in human liver cells in culture with CBO being approximately 100-fold more potent than CHB. In the present study, CBO was shown to react readily with 2'-deoxycytidine (dC) under in vitro physiological conditions (pH 7.4, 37 °C) to form four dC adducts with the CBO moieties forming fused rings with the N3 and N(4) atoms of dC. The four products were structurally characterized as 2-hydroxy-2-hydroxymethyl-7-(2-deoxy-β-d-erythro-pentofuranosyl)-1,2,3,4-tetrahydro-6-oxo-6H,7H-pyrimido[1,6-a]pyrimidin-5-ium (dC-1 and dC-2, a pair of diastereomers), 4-chloromethyl-4-hydroxy-7-(2-deoxy-β-d-erythro-pentofuranosyl)-1,2,3,4-tetrahydro-6-oxo-6H,7H-pyrimido[1,6-a]pyrimidin-5-ium (dC-3), and 2-chloromethyl-2-hydroxy-7-(2-deoxy-β-d-erythro-pentofuranosyl)-1,2,3,4-tetrahydro-6-oxo-6H,7H-pyrimido[1,6-a]pyrimidin-5-ium (dC-4). Interestingly, dC-1 and dC-2 were stable under our experimental conditions (pH 7.4, 37 °C, and 6 h) and existed in equilibrium as indicated by HPLC analysis, whereas dC-3 and dC-4 were labile with the half-lives being 3.0 ± 0.36 and 1.7 ± 0.06 h, respectively. Decomposition of dC-4 produced both dC-1 and dC-2, whereas acid hydrolysis of dC-1/dC-2 and dC-4 in 1 M HCl at 100 °C for 30 min yielded the deribosylated adducts dC-1H/dC-2H and dC-4H, respectively. Because fused-ring dC adducts of other chemicals are mutagenic, the characterized CBO-dC adducts could be mutagenic and play a role in the cytotoxicity and genotoxicity of CBO and its precursors, CHB and BD. The CBO-dC adducts may also be used as standards to characterize CBO-DNA adducts and to develop potential biomarkers for CBO formation in vivo.
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University , Shanghai 200444, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Avishay
authors.initials: A
authors.lastname: Pelah
authors.forename: Dong-Ping
authors.initials: DP
authors.lastname: Zhang
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Zhong
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Ying-Xin
authors.initials: YX
authors.lastname: Yu
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Elfarra
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002070:Butadienes / Q000737:chemistry / Q000378:metabolism*; D002074:Butanones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D021241:Spectrometry, Mass, Electrospray Ionization; D013696:Temperature; D013997:Time Factors
chemical_list: C580717:1-chloro-3-buten-2-one; D015415:Biomarkers; D002070:Butadienes; D002074:Butanones; D018736:DNA Adducts; D003841:Deoxycytidine; C031763:1,3-butadiene
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