Synthesis and mutagenesis of the butadiene-derived N3 2′-deoxyuridine adducts

Priscilla H. Fernandes, Linda C. Hackfeld, Ivan D. Kozekov, Richard P. Hodge, R. Stephen Lloyd

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

1,3-Butadiene is a known carcinogen and mutagen that acts through a variety of metabolic intermediates that react with DNA, forming stable and unstable lesions on dG, dA, dC, and dT. The N3 2′-deoxyuridine adducts are a highly stable, stereoisomeric mixture of adducts derived from the reaction of cytosine with the monoepoxide metabolite of butadiene, followed by spontaneous deamination. In this study, the phosphoramidites and subsequent oligodeoxynucleotides containing the N3 2′-deoxyuridine adducts have been constructed and characterized. Using a single-stranded shuttle vector DNA, the mutagenic potential of these adducts has been tested following replication in mammalian cells. Replication past the N3 2′-deoxyuridine adducts was found to be highly mutagenic with an overall mutation yield of ∼97%. The major mutations that were observed were C to T transitions and C to A transversions. In vitro, these adducts posed a complete block to both the Klenow fragment of Escherichia coli polymerase I and polymerase ε, while these lesions significantly blocked polymerase δ. These data suggested a possible involvement of bypass polymerases in the in vivo replication of these lesions. Overall, these findings indicate that the N3 2′-deoxyuridine adducts are highly mutagenic lesions that may contribute to butadiene-mediated carcinogenesis.

Original languageEnglish (US)
Pages (from-to)968-976
Number of pages9
JournalChemical Research in Toxicology
Volume19
Issue number7
DOIs
StatePublished - Jul 2006

Fingerprint

Deoxyuridine
Mutagenesis
DNA Polymerase I
Genetic Vectors
Deamination
Mutation
Oligodeoxyribonucleotides
Cytosine
DNA
Mutagens
Metabolites
Carcinogens
Escherichia coli
Carcinogenesis
Cells
1,3-butadiene

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Fernandes, P. H., Hackfeld, L. C., Kozekov, I. D., Hodge, R. P., & Lloyd, R. S. (2006). Synthesis and mutagenesis of the butadiene-derived N3 2′-deoxyuridine adducts. Chemical Research in Toxicology, 19(7), 968-976. https://doi.org/10.1021/tx060016o

Synthesis and mutagenesis of the butadiene-derived N3 2′-deoxyuridine adducts. / Fernandes, Priscilla H.; Hackfeld, Linda C.; Kozekov, Ivan D.; Hodge, Richard P.; Lloyd, R. Stephen.

In: Chemical Research in Toxicology, Vol. 19, No. 7, 07.2006, p. 968-976.

Research output: Contribution to journalArticle

Fernandes, PH, Hackfeld, LC, Kozekov, ID, Hodge, RP & Lloyd, RS 2006, 'Synthesis and mutagenesis of the butadiene-derived N3 2′-deoxyuridine adducts', Chemical Research in Toxicology, vol. 19, no. 7, pp. 968-976. https://doi.org/10.1021/tx060016o
Fernandes, Priscilla H. ; Hackfeld, Linda C. ; Kozekov, Ivan D. ; Hodge, Richard P. ; Lloyd, R. Stephen. / Synthesis and mutagenesis of the butadiene-derived N3 2′-deoxyuridine adducts. In: Chemical Research in Toxicology. 2006 ; Vol. 19, No. 7. pp. 968-976.
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