title: Identification and characterization of a series of nucleoside adducts formed by the reaction of 2'-deoxyguanosine and 1,2,3,4-diepoxybutane under physiological conditions.
abstract: The carcinogenicity of 1,3-butadiene (BD) has been attributed to its in vivo metabolites, 3,4-epoxy-1-butene (EB) and 1,2,3,4-diepoxybutane (DEB). In this study, DEB was demonstrated to react with 2'-deoxyguanosine (dG) under in vitro physiological conditions (pH 7.4, 37 degrees C) to yield several pairs of diastereomeric adducts, including N-(2-hydroxy-1-oxiranylethyl)-2'-deoxyguanosine (P4-1 and P4-2), 7,8-dihydroxy-3-(2-deoxy-beta-d-erythro-pentofuranosyl)-3,5,6,7,8,9-hexahydro-1,3-diazepino[1,2-a]purin-11(11H)one (P6), 1-(2-hydroxy-2-oxiranylethyl)-2'-deoxyguanosine (P8 and P9), 1-[3-chloro-2-hydroxy-1-(hydroxymethyl)propyl]-2'-deoxyguanosine (1AP9 and 2AP9), and 4,8-dihydroxy-1-(2-deoxy-beta-d-erythro-pentofuranosyl)-9-hydroxymethyl-6,7,8,9-tetrahydro-1H-pyrimido[2,1-b]purinium ion (1BP4 and 2BP4). The 7-alkylation dG adducts (P5 and P5') were not characterized directly by NMR spectrometry because of their instability. However, their formula weights were determined to be 354, and their acid hydrolysis products were characterized as 2-amino-7-(3-chloro-2,4-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H3), consistent with the structures of P5 and P5' being diastereomers of 6-oxo-2-amino-9-(2-deoxy-beta-d-erythro-pentofuranosyl)-7-(2-hydroxy-2-oxiranylethyl)-6,9-dihydro-1H-purinium ion. Time-course experiments indicated that alkaline pH and/or high DEB:dG molar ratios made the reactions faster without changing the adduct profile. The adducts were detected in the following chronological order: 7- (P5 and P5'), 1- (P8 and P9), N(2)- (P4-1 and P4-2), and P6. Whereas P4-1, P4-2, and P6 appeared stable during the courses of the reactions, P5, P5', P8, and P9 were labile and completely decomposed by the time dG was fully consumed. These results may contribute to a better understanding of the chemical reactivity and strong mutagenicity and carcinogenicity of DEB.
authors.affiliation: Department of Comparative Biosciences and the Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Elfarra
mesh_terms: D000478:Alkylation; D002851:Chromatography, High Pressure Liquid; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D009705:Nucleosides / Q000737:chemistry
chemical_list: D004852:Epoxy Compounds; D009705:Nucleosides; C007366:diepoxybutane; D003849:Deoxyguanosine