Reaction of 1,2,3,4-diepoxybutane with 2'-deoxyguanosine: initial products and their stabilities and decomposition patterns under physiological conditions.

Abstract

1,2,3,4-Diepoxybutane (DEB), an in vivo metabolite of 1,3-butadiene (BD), is a carcinogen and a potent mutagen. Previously, DEB was shown to react with 2'-deoxyguanosine (dG) under physiological conditions to produce seven major nucleoside adducts resulting from alkylation at the N1- (P8 and P9), N7- (P5 and P5'), and both the N1- and the N2-positions of dG to form six-membered (P4-1 and P4-2) and seven-membered fused ring systems (P6), respectively [Zhang, X.-Y., and Elfarra, A. A. (2003) Chem. Res. Toxicol. 16, 1606. Zhang, X.-Y., and Elfarra, A. A. (2004) Chem. Res. Toxicol. 17, 521]. In the present study, the stabilities and decomposition products of the seven adducts under in vitro physiological conditions (phosphate buffer containing KCl, pH 7.4, 37 degrees C) were investigated. The results showed that P4-1, P4-2, and P6 were stable, whereas P5, P5', P8, and P9 were labile with half-lives of 2.6, 2.7, 16, and 16 h, respectively. P5 and P5' decomposed initially by the loss of the deoxyribose moiety to yield the corresponding guanine adduct P5D, which exhibited a half-life of 33 h and decomposed through opening of the remaining oxirane ring by dihydrogen phosphate ion, water, or chloride ion. Decomposition of P8 yielded P4-1, P6, and nucleoside products resulting from opening of the oxirane ring by dihydrogen phosphate ion, water, or chloride ion. Similarly, decomposition of P9 led to the formation of P4-2, P6, and nucleoside products resulting from opening of the oxirane ring by dihydrogen phosphate ion, water, or chloride ion. These results indicate that the initial products of the reaction of DEB with dG are P5, P5', P8, and P9, whereas P4-1, P4-2, and P6 are secondary products. The results may also facilitate development of useful biomarkers of exposure to DEB.