Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts

Ana M. Sanchez, Irina Minko, Andrew J. Kurtz, Manorama Kanuri, Masaaki Moriya, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically γ-hydroxypropanodeoxyguanosine (γ-HOPdG) and α-hydroxypropanodeoxyguanosine (α-HOPdG). While previous investigations have focused on the major γ-HOPdG adduct, little is known about the properties of the minor α-HOPdG adduct. Therefore, this comparative investigation has assessed the following: the ability of each adduct to undergo secondary chemical reactions with biomolecules to form various cross-linked species, in vitro translesion DNA synthesis, and mutagenic properties, following replication in mammalian cells. In contrast to γ-HOPdG, which is capable of forming DNA - DNA, DNA - peptide, and DNA - protein cross-links, α-HOPdG did not form any of these cross-linked species. These results can be attributed to the inability of the α-HOPdG adduct to undergo ring opening, whereas the γ-HOPdG adduct forms the ring open, acyclic N2 oxopropyl in duplex DNA, which readily reacts with nucleophilic functions. Consistent With this interpretation, when polymerase η replication bypass of DNA containing α-HOPdG was assayed, this lesion posed a stronger block to replication than the γ-HOPdG adduct, closely resembling the results for polymerase η bypass of propanodeoxyguanosine in which the exocyclic adduct remains permanently ring-closed. Cellular replication and mutagenesis assays in COS-7 cells using single-stranded DNA containing a site specific α-HOPdG revealed that this adduct was significantly mutagenic, yielding a nearly identical frequency and spectrum of mutations as compared with the γ-HOPdG adduct.

Original languageEnglish (US)
Pages (from-to)1019-1028
Number of pages10
JournalChemical Research in Toxicology
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

Fingerprint

Acrolein
Deoxyguanosine
DNA
Environmental Pollutants
DNA Adducts
Single-Stranded DNA
COS Cells
Mutation Rate
Mutagenesis
DNA Replication
Biomolecules
Lipid Peroxidation
Chemical reactions
Assays
Cells
Peptides
Lipids

ASJC Scopus subject areas

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

Cite this

Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts. / Sanchez, Ana M.; Minko, Irina; Kurtz, Andrew J.; Kanuri, Manorama; Moriya, Masaaki; Lloyd, Robert (Stephen).

In: Chemical Research in Toxicology, Vol. 16, No. 8, 01.08.2003, p. 1019-1028.

Research output: Contribution to journalArticle

Sanchez, Ana M. ; Minko, Irina ; Kurtz, Andrew J. ; Kanuri, Manorama ; Moriya, Masaaki ; Lloyd, Robert (Stephen). / Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts. In: Chemical Research in Toxicology. 2003 ; Vol. 16, No. 8. pp. 1019-1028.
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abstract = "Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically γ-hydroxypropanodeoxyguanosine (γ-HOPdG) and α-hydroxypropanodeoxyguanosine (α-HOPdG). While previous investigations have focused on the major γ-HOPdG adduct, little is known about the properties of the minor α-HOPdG adduct. Therefore, this comparative investigation has assessed the following: the ability of each adduct to undergo secondary chemical reactions with biomolecules to form various cross-linked species, in vitro translesion DNA synthesis, and mutagenic properties, following replication in mammalian cells. In contrast to γ-HOPdG, which is capable of forming DNA - DNA, DNA - peptide, and DNA - protein cross-links, α-HOPdG did not form any of these cross-linked species. These results can be attributed to the inability of the α-HOPdG adduct to undergo ring opening, whereas the γ-HOPdG adduct forms the ring open, acyclic N2 oxopropyl in duplex DNA, which readily reacts with nucleophilic functions. Consistent With this interpretation, when polymerase η replication bypass of DNA containing α-HOPdG was assayed, this lesion posed a stronger block to replication than the γ-HOPdG adduct, closely resembling the results for polymerase η bypass of propanodeoxyguanosine in which the exocyclic adduct remains permanently ring-closed. Cellular replication and mutagenesis assays in COS-7 cells using single-stranded DNA containing a site specific α-HOPdG revealed that this adduct was significantly mutagenic, yielding a nearly identical frequency and spectrum of mutations as compared with the γ-HOPdG adduct.",
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T1 - Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts

AU - Sanchez, Ana M.

AU - Minko, Irina

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AU - Moriya, Masaaki

AU - Lloyd, Robert (Stephen)

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N2 - Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically γ-hydroxypropanodeoxyguanosine (γ-HOPdG) and α-hydroxypropanodeoxyguanosine (α-HOPdG). While previous investigations have focused on the major γ-HOPdG adduct, little is known about the properties of the minor α-HOPdG adduct. Therefore, this comparative investigation has assessed the following: the ability of each adduct to undergo secondary chemical reactions with biomolecules to form various cross-linked species, in vitro translesion DNA synthesis, and mutagenic properties, following replication in mammalian cells. In contrast to γ-HOPdG, which is capable of forming DNA - DNA, DNA - peptide, and DNA - protein cross-links, α-HOPdG did not form any of these cross-linked species. These results can be attributed to the inability of the α-HOPdG adduct to undergo ring opening, whereas the γ-HOPdG adduct forms the ring open, acyclic N2 oxopropyl in duplex DNA, which readily reacts with nucleophilic functions. Consistent With this interpretation, when polymerase η replication bypass of DNA containing α-HOPdG was assayed, this lesion posed a stronger block to replication than the γ-HOPdG adduct, closely resembling the results for polymerase η bypass of propanodeoxyguanosine in which the exocyclic adduct remains permanently ring-closed. Cellular replication and mutagenesis assays in COS-7 cells using single-stranded DNA containing a site specific α-HOPdG revealed that this adduct was significantly mutagenic, yielding a nearly identical frequency and spectrum of mutations as compared with the γ-HOPdG adduct.

AB - Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically γ-hydroxypropanodeoxyguanosine (γ-HOPdG) and α-hydroxypropanodeoxyguanosine (α-HOPdG). While previous investigations have focused on the major γ-HOPdG adduct, little is known about the properties of the minor α-HOPdG adduct. Therefore, this comparative investigation has assessed the following: the ability of each adduct to undergo secondary chemical reactions with biomolecules to form various cross-linked species, in vitro translesion DNA synthesis, and mutagenic properties, following replication in mammalian cells. In contrast to γ-HOPdG, which is capable of forming DNA - DNA, DNA - peptide, and DNA - protein cross-links, α-HOPdG did not form any of these cross-linked species. These results can be attributed to the inability of the α-HOPdG adduct to undergo ring opening, whereas the γ-HOPdG adduct forms the ring open, acyclic N2 oxopropyl in duplex DNA, which readily reacts with nucleophilic functions. Consistent With this interpretation, when polymerase η replication bypass of DNA containing α-HOPdG was assayed, this lesion posed a stronger block to replication than the γ-HOPdG adduct, closely resembling the results for polymerase η bypass of propanodeoxyguanosine in which the exocyclic adduct remains permanently ring-closed. Cellular replication and mutagenesis assays in COS-7 cells using single-stranded DNA containing a site specific α-HOPdG revealed that this adduct was significantly mutagenic, yielding a nearly identical frequency and spectrum of mutations as compared with the γ-HOPdG adduct.

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