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Identification of adducts derived from reactions of (1-chloroethenyl)oxirane with nucleosides and calf thymus DNA

Lookup NU author(s): Dr Tony Munter, Professor William Watson, Emeritus Professor Bernard Golding


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(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 1H and 13C 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 N6-(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 9630 (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.

Publication metadata

Author(s): Munter T, Cottrell L, Hill S, Kronberg L, Watson WP, Golding BT

Publication type: Article

Publication status: Published

Journal: Chemical Research in Toxicology

Year: 2002

Volume: 15

Issue: 12

Pages: 1549-1560

ISSN (print): 0893-228X

ISSN (electronic): 1520-5010

Publisher: American Chemical Society


DOI: 10.1021/tx020070e

PubMed id: 12482237


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