DNA interstrand cross-linking activity of (1-Chloroethenyl)oxirane, a metabolite of beta-chloroprene.
With the goal of elucidating the molecular and cellular mechanisms of chloroprene toxicity, we examined the potential DNA cross-linking of the bifunctional chloroprene metabolite, (1-chloroethenyl)oxirane (CEO). We used denaturing polyacrylamide gel electrophoresis to monitor the possible formation of interstrand cross-links by CEO within synthetic DNA duplexes. Our data suggest interstrand cross-linking at deoxyguanosine residues within 5'-GC and 5'-GGC sites, with the rate of cross-linking depending on pH (pH 5.0 > pH 6.0 > pH 7.0). A comparison of the cross-linking efficiencies of CEO and the structurally similar cross-linkers diepoxybutane (DEB) and epichlorohydrin (ECH) revealed that DEB > CEO > or = ECH. Furthermore, we found that cytotoxicity correlates with cross-linking efficiency, supporting a role for interstrand cross-links in the genotoxicology of chloroprene.
Wadugu
Brian A
BA
Department of Chemistry, Colby College, Waterville, Maine 04901, USA.
Ng
Christopher
C
Bartley
Bethany L
BL
Rowe
Rebecca J
RJ
Millard
Julie T
JT
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002645:Chickens; D002737:Chloroprene / Q000737:chemistry / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000633:toxicity; D004247:DNA / Q000737:chemistry*; D005027:Ethylene Oxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D013234:Stem Cells / Q000187:drug effects
C439367:(1-chloroethenyl)oxirane; D003432:Cross-Linking Reagents; D002737:Chloroprene; D004247:DNA; D005027:Ethylene Oxide