The genotoxicity of 1,3-butadiene is attributed to cytochrome P450-mediated oxidation to di-epoxybutanes (DEB). DEB act as bis-alkylating agents in DNA.  The predominant DEB-induced cross-links involve bis-alkylation at N7-dG in 5'-GNC-3' sequences. Additionally, Tretyakova and co-workers have characterized regioisomeric DEB-induced adenine-guanine cross-links, including N7-dG-N6-dA crosslinks.  The DNA cross-links with labile N7-dG linkages have not been accessible for structural analyses.  My laboratory has used 2R,2R- and 2S,2S-1,4-bis(2'-deoxyadenosin-N6-yl)-butanediol crosslinks prepared by T.M. Harris and co-workers as surrogates, in comparison to non-cross-linked N6-dA butadiene triols. The DNA is not significantly bent by these four carbon crosslinks.  However, the diasteromeric crosslinks exhibit conformational differences.  More recently, my laboratory has examined the DEB-induced exocyclic dA bis-alkylation products N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (R,R-N6,N6-DHB-dA and S,S-N6,N6-DHB-dA), as prepared by Tretyakova and co-workers. These exhibit conformational disruptions that disrupt Watson-Crick hydrogen bonding and destabilize the DNA. Supported by NIH grant ES-05509 (M.P.S.).

Major groove DNA bis-alkylation products arising from diepoxybutane

244th National Meeting (2012)

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