title: Identification of adducts derived from reactions of (1-chloroethenyl)oxirane with nucleosides and calf thymus DNA.
abstract: (1-Chloroethenyl)oxirane is a major mutagenic metabolite of chloroprene, an important large-scale petrochemical used in the manufacture of synthetic rubbers. The reactions of (1-chloroethenyl)oxirane with 2'-deoxyguanosine, 2'-deoxyadenosine, 2'-deoxycytidine, thymidine, and calf thymus DNA have been studied in aqueous buffered solutions. The adducts from the nucleosides were isolated by reversed-phase HPLC, and characterized by their UV absorbance and (1)H and (13)C NMR spectroscopic and mass spectrometric features. The reaction with 2'-deoxyguanosine gave one major adduct, N7-(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (dGI), and eight minor adducts which were identified as diastereoisomeric pairs of N1-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyguanosine (dGII, dGIII), N3,N7-bis(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (dGIV, dGV), N7,N9-bis(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (dGVI, dGVII), and N1,N7-bis(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (dGVIII, dGIX). The reaction of 2'-deoxyadenosine with (1-chloroethenyl)oxirane gave two adducts: N1-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine (dAI) and N(6)-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine (dAII). The adduct dAII was shown to arise via a Dimroth rearrangement of adduct dAI. The HPLC analyses of the reaction mixtures of (1-chloroethenyl)oxirane with 2'-deoxycytidine and thymidine showed the formation of one major product in each reaction. The adduct from 2'-deoxycytidine was identified as N3-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyuridine (dCI) derived by alkylation at N-3 followed by deamination. The adduct from thymidine was identified as N3-(3-chloro-2-hydroxy-3-buten-1-yl)-thymidine (TI). Reaction of (1-chloroethenyl)oxirane with calf thymus DNA gave all of the adducts observed from the individual nucleosides except dGII and dGIII. However, there was selectivity for the formation of dGI and dCI. The adduct levels in DNA were 9,630 (dGI), 240 (dCI), 83 (dAI), 6 (dAII), and 28 (TI) pmol/mg DNA, respectively. The preferred formation of dCI may be relevant to chloroprene mutagenesis.
authors.affiliation: Department of Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Munter
authors.forename: Lisa
authors.initials: L
authors.lastname: Cottrell
authors.forename: Stuart
authors.initials: S
authors.lastname: Hill
authors.forename: Leif
authors.initials: L
authors.lastname: Kronberg
authors.forename: William P
authors.initials: WP
authors.lastname: Watson
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
mesh_terms: D000478:Alkylation; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism*; D003641:Deamination; D003853:Deoxyribonucleosides / Q000737:chemistry / Q000378:metabolism*; D005027:Ethylene Oxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D009153:Mutagens / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
chemical_list: C439367:(1-chloroethenyl)oxirane; D018736:DNA Adducts; D003853:Deoxyribonucleosides; D009153:Mutagens; D004247:DNA; C427203:calf thymus DNA; D005027:Ethylene Oxide