Detoxification of olefinic epoxides and nucleotide excision repair of epoxide-mediated DNA damage: Insights from animal models examining human sensitivity to 1,3-butadiene

Jeffrey K. Wickliffe, Stacy M. Herring, Lance M. Hallberg, Lori A. Galbert, Oscar E. Masters, Marinel M. Ammenheuser, Jingwu Xie, Errol C. Friedberg, R. Stephen Lloyd, Sherif Z. Abdel-Rahman, Jonathan B. Ward

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

1,3-Butadiene (BD) is a well-documented mutagen and carcinogen in rodents and is currently classified as a probable carcinogen in humans. Studies investigating workers exposed to BD indicate that, in some plants, there may be an increased genetic risk, and that polymorphisms in biotransformation and DNA repair proteins may modulate genetic susceptibility. To investigate the role of genetic polymorphisms in microsomal epoxide hydrolase (mEH) or nucleotide excision repair (NER) in contributing to the mutagenicity of BD, we conducted a series of experiments in which mice lacking mEH or NER activity were exposed to BD by inhalation or to the reactive epoxide metabolites of BD (epoxybutene-EB or diepoxybutane-DEB) by i.p. injection. Genetic susceptibility was measured using the Hprt cloning assay. Both deficient strains of mouse were significantly more sensitive to the mutagenic effects of BD and the injected epoxides. These studies provide support for the critical role that mEH plays in the biotransformation of BD, and the role that NER plays in maintaining genomic integrity following exposure to BD. Additional studies are needed to examine the importance of base excision repair (BER) in maintaining genomic integrity, the differential formation of DNA and protein adducts in deficient strains, and the potential for enhanced sensitivity to BD genotoxicity in mice either lacking or deficient in both biotransformation and DNA repair activity.

Original languageEnglish (US)
Pages (from-to)226-231
Number of pages6
JournalChemico-Biological Interactions
Volume166
Issue number1-3
DOIs
StatePublished - Mar 20 2007
Externally publishedYes

Keywords

  • Biotransformation
  • Butadiene
  • Epoxide
  • Epoxide hydrolase
  • Hprt
  • Inhalation
  • Mice
  • Mutagenicity
  • Nucleotide excision repair
  • Xpc

ASJC Scopus subject areas

  • Toxicology

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  • Cite this

    Wickliffe, J. K., Herring, S. M., Hallberg, L. M., Galbert, L. A., Masters, O. E., Ammenheuser, M. M., Xie, J., Friedberg, E. C., Lloyd, R. S., Abdel-Rahman, S. Z., & Ward, J. B. (2007). Detoxification of olefinic epoxides and nucleotide excision repair of epoxide-mediated DNA damage: Insights from animal models examining human sensitivity to 1,3-butadiene. Chemico-Biological Interactions, 166(1-3), 226-231. https://doi.org/10.1016/j.cbi.2006.04.017