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

Ana M. Sanchez, Irina G. Minko, Andrew J. Kurtz, Manorama Kanuri, Masaaki Moriya, R. Stephen Lloyd

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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

ASJC Scopus subject areas

  • Toxicology

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