Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts

David A. Rodriguez, Agnieszka Kowalczyk, Jonathan B. Ward, Constance M. Harris, Thomas M. Harris, R. Stephen Lloyd

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The National Toxicology Program has recently classified 1,3-butadiene (BD) as a human carcinogen. BD is metabolized to the intermediates 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-dihydroxy-3,4-epoxybutane. All three metabolites have been implicated in producing specific types of DNA damage and as genotoxic agents in mice, rat, and human cells. This study has focused on EB-induced N1 deoxyinosine lesions that are formed by deamination of deoxyadenosine following reaction of the epoxide at the N1 position. The R and S stereoisomers of this lesion were incorporated site-specifically within the context of an 11-mer oligodeoxynucleotide, incorporated into M13mp7L2 single-stranded DNA, and transfected into E. coli. Both stereoisomers modestly reduced plaque-forming ability, indicating that neither lesion presents a base modification that cannot be bypassed. The resulting plaques were assessed for point mutations using differential hybridization and DNA sequence analyses. The overall mutagenic spectrum revealed that the N1 adducts were highly mutagenic (∼90% per replication cycle), causing a predominance of A → G transitions.

Original languageEnglish (US)
Pages (from-to)292-296
Number of pages5
JournalEnvironmental and Molecular Mutagenesis
Volume38
Issue number4
DOIs
StatePublished - 2001

Keywords

  • 1,3-butadiene adducts
  • Deoxyoligonucleotides
  • Mutagenesis
  • Mutational spectrum
  • N-inosine

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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