AM1 computational study on metabolites of 1,3-butadiene interstrand cross-linking DNA

The alkylating reactions of 1,2-epoxy-3,4-butene (EB) and 1,2,3,4-diepoxybu tane (DEB)-the important metabolites of rodent carcinogenic 1,3-butadiene, with adenine and cytosine and interaction with fragment of DNA on major gro ove-have been computed. Results show that there are little differences in a ctivation energy between EB and DEB, so it is difficult to explain the fact that the mutagenicity of DEB is greater (about 100-fold) than that of EB b y the ability of alkylation. It is also known that DEB can interstrand cros s-link with DNA through two times alkylating reactions, whereas EB cannot. So this may contribute to the significant different genotoxicity of the two agents. Meanwhile, DEB can interstrand cross-link with many sequences of D NA in major groove vs. two in minor groove, which increases opportunity of interstrand cross-link with DNA in major groove. This difference may be the reason of base selection of DEB mutation. The deformation of some cross-li nked DNA may also contribute to this selection to some degree.