DNA interstrand cross-linking activity of (1-Chloroethenyl)oxirane, a metabolite of beta-chloroprene

Chem Res Toxicol. 2010 Jan;23(1):235-9. doi: 10.1021/tx9003769.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cells, Cultured
  • Chickens
  • Chloroprene / chemistry
  • Chloroprene / metabolism*
  • Cross-Linking Reagents / chemistry*
  • Cross-Linking Reagents / toxicity
  • DNA / chemistry*
  • Ethylene Oxide / analogs & derivatives*
  • Ethylene Oxide / chemistry
  • Ethylene Oxide / toxicity
  • Hydrogen-Ion Concentration
  • Stem Cells / drug effects

Substances

  • (1-chloroethenyl)oxirane
  • Cross-Linking Reagents
  • Chloroprene
  • DNA
  • Ethylene Oxide