title: Characterization of the reaction products of 2'-deoxyguanosine and 1,2,3,4-diepoxybutane after acid hydrolysis: formation of novel guanine and pyrimidine adducts.
abstract: 1,2,3,4-diepoxybutane (DEB), an important in vivo metabolite of 1,3-butadiene (BD), is a potent mutagen and a known carcinogen. Recently, DEB has been shown to react with 2'-deoxyguanosine (dG) at 37 degrees C and pH 7.4 to yield a series of nucleoside adducts, resulting from alkylation at the 7-, 1-, and N(2)-positions of dG. In addition, adducts with fused ring systems are formed. In the present study, new adducts are characterized after DEB was allowed to react with dG at pH 7.4 and the reaction mixture was then subjected to acid hydrolysis. These adducts are 7-hydroxy-6-hydroxymethyl-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(1H)one (H2), 2-amino-1-(4-chloro-2,3-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H4), 2-amino-1-(2,3,4-trihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H1'/H5'), 7,8-dihydroxy-1,5,6,7,8,9-hexahydro-1,3-diazepino[1,2-a]purin-11(11H)one (H2'), and 5-(3,4-dihydroxy-1-pyrrolidinyl)-2,6-diamino-4(3H)pyrimidinone (H3'). The previously characterized guanine adducts, 2-amino-7-(3-chloro-2,4-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H3) and 2-amino-7-(2,3,4-trihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H4'), were also detected. Acid hydrolysis of purified dG-DEB adducts confirmed that H2, H3/H4', H2', and H4/H1'/H5' are the hydrolysis products of N-(2-hydroxy-1-oxiranylethyl)-2'-deoxyguanosine (P4-1 and P4-2), 6-oxo-2-amino-9-(2-deoxy-beta-d-erythro-pentofuranosyl)-7-(2-hydroxy-2-oxiranylethyl)-6,9-dihydro-1H-purinium ion (P5 and P5'), 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), and 1-(2-hydroxy-2-oxiranylethyl)-2'-deoxyguanosine (P8 and P9), respectively. On the other hand, the novel pyrimidine adduct H3' is formed by the decomposition of P5 and P5' during the incubation and hydrolysis. These results may facilitate the development of useful biomarkers of exposure to DEB and its precursor BD.
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: D015415:Biomarkers / Q000032:analysis; D002273:Carcinogens / Q000737:chemistry* / Q000633:toxicity; D003849:Deoxyguanosine / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D004852:Epoxy Compounds; C007366:diepoxybutane; D003849:Deoxyguanosine