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

1,2,3,4-Diepoxybutane (DEB) is reported to be the most potent mutagenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant. DEB is capable of inducing the formation of monoalkylated DNA adducts and DNA–DNA and DNA–protein cross-links. We previously reported tha...

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Bibliographic Details
Published in:Chemical research in toxicology 2012-03, Vol.25 (3), p.706-712
Main Authors: Cho, Sung-Hee, Guengerich, F. Peter
Format: Article
Language:English
Subjects:
Animals
Cross-Linking Reagents - metabolism
Cross-Linking Reagents - toxicity
DNA Adducts - analysis
Epoxy Compounds - metabolism
Epoxy Compounds - toxicity
Glutathione - metabolism
Liver - metabolism
Mice
Mutagenicity Tests
Mutagens - metabolism
Mutagens - toxicity
Rats
Rats, Sprague-Dawley
Salmonella typhi - drug effects
Salmonella typhi - genetics
Salmonella typhimurium
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Summary:1,2,3,4-Diepoxybutane (DEB) is reported to be the most potent mutagenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant. DEB is capable of inducing the formation of monoalkylated DNA adducts and DNA–DNA and DNA–protein cross-links. We previously reported that DEB forms a conjugate with glutathione (GSH) and that the conjugate is considerably more mutagenic than several other butadiene-derived epoxides, including DEB, in the base pair tester strain Salmonella typhimurium TA1535 [ Cho (2010) Chem. Res. Toxicol. 23, 1544−1546 ]. In the present study, we determined steady-state kinetic parameters of the conjugation of the three DEB stereoisomersR,R, S,S, and meso (all formed by butadiene oxidation)with GSH by six GSH transferases. Only small differences (
ISSN:0893-228X
1520-5010
DOI:10.1021/tx200471x