Site-specific mutagenicity of stereochemically defined 1, N 2-deoxyguanosine adducts of trans-4-hydroxynonenal in mammalian cells

Priscilla H. Fernandes, Hao Wang, Carmelo J. Rizzo, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Trans-4-hydroxynonenal (HNE) is a toxic compound produced endogenously during lipid peroxidation. HNE is a potent electrophile that is reactive with both proteins and nucleic acids. HNE preferentially reacts with deoxyguanosine to form four stereoisomeric HNE-deoxyguanosine (HNE-dG) adducts: (6R, 8S, 11R), (6S, 8R, 11S), (6R, 8S, 11S), and (6S, 8R, 11R). These adducts were synthesized into 12-mer oligodeoxynucleotides, inserted into a DNA shuttle vector and evaluated for the ability of each stereoisomer to induce mutagenesis when replicated through mammalian cells. The resultant mutagenicity of these adducts was related to their stereochemistry, in that two of the HNE-dG adducts, (6R, 8S, 11R) and (6S, 8R, 11S), were significantly more mutagenic than the (6R, 8S, 11S) and (6S, 8R, 11R) HNE-dG adducts. These data conclusively demonstrate that HNE-derived DNA adducts can be mutagenic in mammalian cells and their ability to cause mutations is dictated by their stereochemistry.

Original languageEnglish (US)
Pages (from-to)68-74
Number of pages7
JournalEnvironmental and Molecular Mutagenesis
Volume42
Issue number2
DOIs
StatePublished - 2003
Externally publishedYes

Fingerprint

Stereochemistry
Deoxyguanosine
mutagenicity
Cells
DNA
Genetic Vectors
Mutagenesis
Stereoisomerism
DNA Adducts
Oligodeoxyribonucleotides
Poisons
nucleic acid
Nucleic Acids
Lipid Peroxidation
mutation
lipid
Lipids
Mutation
protein
Proteins

Keywords

  • HNE-dG adducts
  • Mutagenicity
  • Stereoisomers
  • Trans-4-hydrononenal

ASJC Scopus subject areas

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

Cite this

Site-specific mutagenicity of stereochemically defined 1, N 2-deoxyguanosine adducts of trans-4-hydroxynonenal in mammalian cells. / Fernandes, Priscilla H.; Wang, Hao; Rizzo, Carmelo J.; Lloyd, Robert (Stephen).

In: Environmental and Molecular Mutagenesis, Vol. 42, No. 2, 2003, p. 68-74.

Research output: Contribution to journalArticle

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AB - Trans-4-hydroxynonenal (HNE) is a toxic compound produced endogenously during lipid peroxidation. HNE is a potent electrophile that is reactive with both proteins and nucleic acids. HNE preferentially reacts with deoxyguanosine to form four stereoisomeric HNE-deoxyguanosine (HNE-dG) adducts: (6R, 8S, 11R), (6S, 8R, 11S), (6R, 8S, 11S), and (6S, 8R, 11R). These adducts were synthesized into 12-mer oligodeoxynucleotides, inserted into a DNA shuttle vector and evaluated for the ability of each stereoisomer to induce mutagenesis when replicated through mammalian cells. The resultant mutagenicity of these adducts was related to their stereochemistry, in that two of the HNE-dG adducts, (6R, 8S, 11R) and (6S, 8R, 11S), were significantly more mutagenic than the (6R, 8S, 11S) and (6S, 8R, 11R) HNE-dG adducts. These data conclusively demonstrate that HNE-derived DNA adducts can be mutagenic in mammalian cells and their ability to cause mutations is dictated by their stereochemistry.

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