Butadiene monoxide and deoxyguanosine alkylation products at the N7-position

Abstract

3,4-Epoxy-1-butene, an active metabolite of 1,3-butadiene, was reacted with guanosine, deoxyguanosine and calf thymus DNA. The products were isolated and positively identified using various spectroscopic techniques. Treatment of calf thymus-DNA with 3,4-epoxy-1-butene yielded two N7-guanine adducts of equal stability. Depurination by neutral hydrolysis showed that 7-(2-hydroxy-3-buten-1-yl)guanine (compound I) was formed in greater quantities compared to its regioisomer 7-(1-hydroxy-3-buten-2-yl)guanine (compound II); spontaneous depurination experiments showed that compound I was released in the highest proportion. The circular dichroism spectral studies with R and S 3,4-epoxy-1-butene revealed that the reaction mechanism at aqueous neutral pH media is more similar to SN2-type rather than SN1-type. The HPLC-electrochemical detection method used to carry out the DNA alkylation study provides a rapid and sensitive quantitation of N7 guanine adducts in biological fluids. This serves as a useful tool for further human biomonitoring experiments.

Clerocidin alkylates DNA through its epoxide function: evidence for a fine tuned mechanism of action

“…Molecular masses obtained for these species match 1:1 covalent adducts of 2¢deoxy-guanosine with the different drugs including the loss of the deoxy-ribose moiety ( Table 1). The depurination process is a direct and unique consequence of alkylation at N 7 of guanines, which is routinely used in biochemical sequencing of DNA based on the Maxam and Gilbert protocol (15) and has been reported for carcinogenic alkylators, such as the diol epoxide of benzo(a)pyrene (19), or epoxide-containing drugs (6,20). A plausible mechanism would involve the initial attack of the epoxide to the nucleophilic N 7 of the guanine base.…”

Molecular Dosimetry of N-7 Guanine Adduct Formation in Mice and Rats Exposed to 1,3-Butadiene

“…Numerous DNA adducts of BD, mainly with guanine and adenine, have been reported in the literature. The N-7 guanine adducts of EB (24)(25)(26)(27)(28)(29)(30)(31) and DEB (32), N-1, N-3, N 6 , and N-7 adenine adducts of EB (30,31,(33)(34)(35), and N-3, N 6 , N-7, and N-9 adenine adducts of DEB (36)(37)(38) and N-3-thymidine adducts of EB (39) have been characterized. LC/ESI + /MS/MS (40,41) and 32 P-postlabeling (27,28,34,35,37,(42)(43)(44)(45) combined with chromatographic separation have been used to characterize and/or quantitate the adducts formed in vitro by EB and DEB.…”

Analysis of DNA-bound advanced glycation end-products by LC and mass spectrometry

“…60% formic acid for 30 min at 140 • C) hydrolyzes DNA completely to the nucleobases [50]. In some cases, particularly when guanine or adenine are modified in position N-3 or N-7, the nucleobase adduct can be selectively released from the DNA by thermal hydrolysis, whereas mild acid hydrolysis selectively cleaves the purine bases from the DNA backbone [51]. Furthermore, DNA repair enzymes, mainly formamidopyrimidine glycosylase (Fpg), can be used to cleave selectively nucleobase adducts from the DNA [50].…”