title: A novel DNA adduct, originating from 1,2-epoxy-3,4-butanediol, is the major DNA adduct after exposure to [2,3-(14)C]-1,3-butadiene,[4-(14)C]-1,2-epoxy-3-butane.
abstract: 1,3-Butadiene is a rodent carcinogen and its epoxide metabolites, 1,2-epoxy-3-butene (EB), 1,2-epoxy-3,4-butanediol (EBD), and 1,2:3,4-diepoxybutane (DEB) have been suggested as ultimate carcinogens. This study aimed at identification and quantification of DNA adducts in rats and mice following exposure to BD and its major metabolite EB to identify the reactive epoxide(s) in target tissues. Reaction of [4-(14)C]-EB with 2'-deoxyguanosine (dG) or DNA gave equal amounts of N7-(2-hydroxy-3-butenyl)guanine (G1) and N7-(1-(hydroxymethyl)-2-propenyl)guanine (G2). Reaction of DEB stereomers with dG yielded N7-(2,3,4-trihydroxybutyl)guanine (G3) as major adduct and novel, minor adduct (G4) that was tentatively identified as N7-(1-(hydroxymethyl)-2,3-dihydroxypropyl)guanine. For the stereomers of EBD, the opposite was found: reaction with dG led to G4 as major and G3 as minor adduct. 2D-Total correlation 1H-NMR spectroscopy of G4 indicated that the N7-alkyl group was in a virtually fixed conformational state and might interact with the O(6) of guanine, which might imply a higher degree of mutagenicity of G4, due to G-C mispairing, than of any other adducts observed in this study. At 48 h following exposure to [4-(14)C]-EB (1-50 mg/kg), DNA adduct profiles in rat and mouse were qualitatively similar, with G1 and G2 as main, and G4 as minor adduct. Following nose-only exposure to 200 ppm [2,3-(14)C]-BD for 6 h, G1 and G2 were minor adducts in liver (1.9 and 8.0 per 10(8) nucleotides) and lung (1.6 and 6.6 per 10(8) nucleotides, for rats and mice, respectively). G3 was absent in rats, but present in mouse liver and lung, at 20 and 12 adducts/10(8) nucleotides. The major adduct was G4 accounting for 13 and 90 (liver) and 11 and 139 (lung) adducts/10(8) nucleotides in rats and mice, respectively. Forty-two hours later, these adduct levels had only little changed. Our recent biomarker studies confirm that following exposure to BD, but not BDO, EBD is the major epoxide available for macromolecular binding in humans and rodents. Most probably because EBD is in contrast to EB and DEB, a poor substrate for epoxide hydrolases. In conclusion, the major DNA adduct following exposure to BD is G4, originating from EBD, and not from EB or BDE. It is concluded that EBD and G4 should be taken into account for human risk assessment for exposure to BD.
authors.affiliation: Molecular Toxicology, Shell Research & Technology Centre, Amsterdam, The Netherlands. peter.j.boogaard@si.shell.com
authors.forename: P J
authors.initials: PJ
authors.lastname: Boogaard
authors.forename: N J
authors.initials: NJ
authors.lastname: van Sittert
authors.forename: W P
authors.initials: WP
authors.lastname: Watson
authors.forename: K P
authors.initials: KP
authors.lastname: de Kloe
mesh_terms: D000818:Animals; D002070:Butadienes / Q000633:toxicity*; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry* / Q000187:drug effects*; D004852:Epoxy Compounds / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002070:Butadienes; D002250:Carbon Radioisotopes; D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; C024370:3,4-epoxy-1-butene; C031763:1,3-butadiene