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, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

18 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Stereoisomerism
Point Mutation
lesion
mutation
DNA
Deamination
Oligodeoxyribonucleotides
Single-Stranded DNA
DNA sequences
Epoxy Compounds
Metabolites
Butenes
DNA Sequence Analysis
Carcinogens
Toxicology
Escherichia coli
DNA Damage
Rats
Cells
toxicology

Keywords

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

ASJC Scopus subject areas

  • Environmental Science(all)
  • Environmental Chemistry
  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts. / Rodriguez, David A.; Kowalczyk, Agnieszka; Ward, Jonathan B.; Harris, Constance M.; Harris, Thomas M.; Lloyd, Robert (Stephen).

In: Environmental and Molecular Mutagenesis, Vol. 38, No. 4, 2001, p. 292-296.

Research output: Contribution to journalArticle

Rodriguez, DA, Kowalczyk, A, Ward, JB, Harris, CM, Harris, TM & Lloyd, RS 2001, 'Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts', Environmental and Molecular Mutagenesis, vol. 38, no. 4, pp. 292-296. https://doi.org/10.1002/em.10026
Rodriguez, David A. ; Kowalczyk, Agnieszka ; Ward, Jonathan B. ; Harris, Constance M. ; Harris, Thomas M. ; Lloyd, Robert (Stephen). / Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts. In: Environmental and Molecular Mutagenesis. 2001 ; Vol. 38, No. 4. pp. 292-296.
@article{eaa1f20d399a44abbea193576d8146d5,
title = "Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts",
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.",
keywords = "1,3-butadiene adducts, Deoxyoligonucleotides, Mutagenesis, Mutational spectrum, N-inosine",
author = "Rodriguez, {David A.} and Agnieszka Kowalczyk and Ward, {Jonathan B.} and Harris, {Constance M.} and Harris, {Thomas M.} and Lloyd, {Robert (Stephen)}",
year = "2001",
doi = "10.1002/em.10026",
language = "English (US)",
volume = "38",
pages = "292--296",
journal = "Environmental and Molecular Mutagenesis",
issn = "0893-6692",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts

AU - Rodriguez, David A.

AU - Kowalczyk, Agnieszka

AU - Ward, Jonathan B.

AU - Harris, Constance M.

AU - Harris, Thomas M.

AU - Lloyd, Robert (Stephen)

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - 1,3-butadiene adducts

KW - Deoxyoligonucleotides

KW - Mutagenesis

KW - Mutational spectrum

KW - N-inosine

UR - http://www.scopus.com/inward/record.url?scp=0035681390&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035681390&partnerID=8YFLogxK

U2 - 10.1002/em.10026

DO - 10.1002/em.10026

M3 - Article

VL - 38

SP - 292

EP - 296

JO - Environmental and Molecular Mutagenesis

JF - Environmental and Molecular Mutagenesis

SN - 0893-6692

IS - 4

ER -