Mutagenicity of a Glutathione Conjugate of Butadiene Diepoxide

Abstract

The mutagenicity and carcinogenicity of the important commodity chemical 1,3-butadiene are attributed to the epoxide products. We confirmed our previous work showing that expression of rat glutathione (GSH) transferase 5-5 enhances the mutagenicity of butadiene diepoxide in Salmonella typhimurium TA1535. A GSH-butadiene diepoxide was isolated and fully characterized by mass spectrometry and NMR as S-(2-hydroxy-3,4-epoxybutyl)GSH. The conjugate had a t1/2 of 2.6 h (pH 7.4, 37 °C) and was considerably more mutagenic than butadiene diepoxide or monoepoxide in S. typhimurium. We propose that the GSH conjugate may be a major species involved in butadiene genotoxicity, not a detoxication product.

Mutation Spectra of S-(2-Hydroxy-3,4-epoxybutyl)glutathione: Comparison with 1,3-Butadiene and Its Metabolites in the Escherichia coli rpoB Gene

“…The frequencies of rifampicin-resistant mutants generated by the BD/mouse liver microsomes/GST/GSH system and the DEB/GST/GSH system, as well as the DEB-GSH conjugate, were higher than those of all other systems absent of GST, in agreement with the higher mutagenicities of DEB following GST expression 19,20 and the higher mutagenicity of the DEB-GSH conjugate than DEB or several other butadiene-derived epoxides in S. typhimurium TA1535. 21 These results indicate that GSH conjugation enhances the mutagenicity of BD by formation of cross-links between DNA and GSH induced by DEB.…”

“…20 Significantly higher mutagenicity of the synthetic S -(2-hydroxy-3,4-epoxybutyl)GSH (DEB-GSH) conjugate was measured compared to several other butadiene-derived epoxides, including DEB, in S. typhimurium TA1535. 21 Six DNA adducts— S -[4-( N 3 -adenyl)-2,3-dihydroxybutyl]GSH (N 3 A-(OH) 2 butyl-GSH), S -[4-( N 6 -deoxyadenosinyl)-2,3-dihydroxybutyl]GSH (N 6 dA-(OH) 2 butyl-GSH), S -[4-( N 7 -guanyl)-2,3-dihydroxybutyl]GSH (N 7 G-(OH) 2 butyl-GSH), S -[4-( N 1 -deoxyguanosinyl)-2,3-dihydroxybutyl]GSH (N 1 dG-(OH) 2 butyl-GSH), S -[4-( N 4 -deoxycytidinyl)-2,3-dihydroxybutyl]GSH (N 4 dC-(OH) 2 butyl-GSH,), and S -[4-( N 3 -thymidinyl)-2,3-dihydroxybutyl]GSH (N 3 dT-(OH) 2 butyl-GSH)—were identified in the reaction of the DEB-GSH conjugate with nucleosides and calf thymus DNA, and two of the adducts—N 6 dA-(OH) 2 butyl-GSH and N 7 G-(OH) 2 butyl-GSH—were identified and quantitated in vivo in the livers of mice and rats treated with DEB. 22 These results suggest that a GSH conjugate of DEB reacts with DNA and is a major mutagen with biological activity as great or greater than other BD oxidation products, including DEB, and therefore expected to contribute to the carcinogenicity of DEB.…”

Conjugation of Butadiene Diepoxide with Glutathione Yields DNA Adducts in Vitro and in Vivo

“…43,44 We previously reported a dramatic enhancement of base pair mutagenicity of DEB following GST expression in Salmonella typhimurium TA1535, 30,31 and subsequently a synthetic DEB-GSH conjugate was formed to be considerably more mutagenic than DEB or several other butadiene-derived epoxides in S. typhimurium TA1535. 32 …”

In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

“…Even though DEB metabolism variation among species is known to be an important determinant of BD-induced carcinogenicity (Fred et al, 2008;US EPA, 2002), other factors such as differences in DNA repair of DNA-DNA cross-links and mutations between gender might contribute to species differences in susceptibility (Pianalto et al, 2013;Swenberg et al, 2011). Another complexity with regard to DEB is the conjugation of glutathione that could cross-link DNA as suggested by Cho et al (2010).…”