Alkyltransferase-mediated toxicity of 1,3-butadiene diepoxide.

Chemical Research in Toxicology
Aley G KalapilaAnthony E Pegg

Abstract

Human O(6)-alkylguanine-DNA alkyltransferase (hAGT) expression increases mutations and cytotoxicity following exposure to 1,3-butadiene diepoxide (BDO), and hAGT-DNA cross-links are formed in the presence of BDO. We have used hAGT mutants to investigate the mechanism of cross-link formation and genotoxicity. Formation of a hAGT-DNA conjugate in vitro was observed with C145S and C145A mutant proteins but was considerably diminished with the C145A/C150S double mutant confirming that cross-linking primarily involves either of these two cysteine residues, which are located in the active site pocket of the protein. Cross-link formation by BDO occurred both via (a) an initial reaction of BDO with hAGT followed by attack of the reactive hAGT complex on DNA, and (b) the initial reaction of BDO with DNA followed by a reaction between hAGT and the DNA adduct. These results differ from those with 1,2-dibromoethane (DBE) where Cys(145) is the only site of attachment and pathway (b) does not occur. The complex formed between hAGT at Cys(145) and BDO was very unstable in aqueous solution. However, the BDO-hAGT complex at Cys(150) exhibited stability for more than 1 h. The effect of hAGT and mutants on BDO-induced genotoxicity was studied in ...Continue Reading

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Citations

Feb 19, 2013·Chemical Research in Toxicology·Matthew R NaticchiaJames D West
Nov 28, 2009·Mutation Research·Aley G Kalapila, Anthony E Pegg
May 28, 2009·Environmental and Molecular Mutagenesis·Aley G KalapilaAnthony E Pegg
Jun 3, 2015·Accounts of Chemical Research·Natalia Y TretyakovaShaofei Ji
Apr 10, 2013·Biochemistry·Natalia Y TretyakovaColin Campbell
Oct 27, 2018·Environmental Microbiology·Özlem AkkayaVíctor de Lorenzo
Oct 15, 2009·International Journal of Environmental Research and Public Health·John J GraffElizabeth Delzell
Sep 28, 2010·Critical Reviews in Toxicology·Richard J AlbertiniMichael L Gargas

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