DNA adducts in rats and mice following exposure to [4- [formula omitted]]-1,2-epoxy-3-butene and to [2,3- [formula omitted]]-1,3-butadiene

Abstract

1,3-Butadiene (BD) is a major industrial chemical and a rodent carcinogen, with mice being much more susceptible than rats. Oxidative metabolism of BD, leading to the DNA-reactive epoxides 1,2-epoxy-3-butene (BMO), 1,2-epoxy-3,4-butanediol (EBD) and 1,2:3,4-diepoxybutane (DEB), is greater in mice than rats. In the present study the DNA adduct profiles in liver and lungs of rats and mice were determined following exposure to BMO and to BD since these profiles may provide qualitative and quantitative information on the DNA-reactive metabolites in target tissues. Adducts detected in vivo were identified by comparison with the products formed from the reaction of the individual epoxides with 2′-deoxyguanosine (dG). In rats and mice exposed to [4- 14 C ]-BMO (1–50 mg/kg, i.p.), DNA adduct profiles were similar in liver and lung with N 7-(2-hydroxy-3-butenyl)guanine ( G1) and N 7-(1-(hydroxymethyl)-2-propenyl)guanine ( G2) as major adducts and N 7-2,3,4-trihydroxybutylguanine ( G4) as minor adduct. In rats and mice exposed to 200 ppm [2,3- 14 C ]-BD by nose-only inhalation for 6 h, G4 was the major adduct in liver, lung and testes while G1 and G2 were only minor adducts. Another N 7-trihydroxybutylguanine adduct ( G3), which could not unambiguously be identified but is either another isomer of N 7-2,3,4-trihydroxybutylguanine or, more likely, N 7-(1-hydroxymethyl-2,3-dihydroxypropyl)guanine, was present at low concentrations in liver and lung DNA of mice, but absent in rats. The evidence indicates that the major DNA adduct formed in liver, lung and testes following in vivo exposure to BD is G4, which is formed from EBD, and not from DEB.