N2,7-bis(1-hydroxy-2-oxopropyl)-2'-deoxyguanosine: identical noncyclic adducts with 1,3-dichloropropene epoxides and methylglyoxal.

cis- and trans-1,3-dichloropropene epoxides (1,3-D-epoxides) are proposed to be the penultimate or ultimate genotoxic metabolites of the major soil fumigant nematicide 1,3-dichloropropene. The 1, 3-D-epoxide isomers and the potential aldehydes from their degradation readily form adducts with 2'-deoxyguanosine (dGuo) but not with 2'-deoxyadenosine or 2'-deoxycytidine. The reaction of dGuo with the 1,3-D-epoxides (1:20 molar equiv) in phosphate buffer at pH 7.4 for 24 h at 37 degreesC results in complete conversion to four adducts that can be separated by HPLC with the same UV spectra and electrospray (ES)/MS molecular ion and fragmentation patterns. These adducts contain no chlorine and are identical to those obtained more rapidly with methylglyoxal in place of the 1,3-D-epoxides. The four isomeric methylglyoxal adducts with dGuo were proposed originally by others to be the cyclic adducts 1,N2-(1, 2-dihydroxy-2-methyl)ethano-dGuo, but they are reassigned here as the four diastereomers of the noncyclic bis adducts N2, 7-bis(1-hydroxy-2-oxopropyl)-dGuo. The assignments are based on HPLC/UV and HPLC/ES/MS experiments and 1H NMR spectral analysis of the first of the four adducts eluted with HPLC. Acid-catalyzed depurination converts the four dGuo derivatives to the two corresponding isomers of N2,7-bis(1-hydroxy-2-oxopropyl)guanine, assigned by ES/MS and 1H and 13C NMR. Although identical adducts are formed from dGuo with the 1,3-D-epoxides or methylglyoxal, the latter alpha,beta-dicarbonyl compound is not an intermediate in the reaction; instead, the 1,3-D-epoxides hydrolyze to 3-chloro-2-hydroxypropanal which adds to dGuo at N2 and N7. The adducts dehydrochlorinate, in a rate-limiting reaction, thereby giving the same end products obtained on direct reaction with methylglyoxal. Thus, 3-chloro-2-hydroxypropanal (not the 1, 3-D-epoxides or methylglyoxal) is the derivatizing agent for dGuo and therefore probably the mutagenic agent on 1,3-D bioactivation. On the basis of the dGuo model studied here, the DNA adducts of 1, 3-D and its epoxides may be the same as those with methylglyoxal [Vaca, C. E., Fang, J.-L., Conradi, M., and Hou, S.-M. (1994) Carcinogenesis 15, 1887-1894].