TY - JOUR
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 G.
AU - Kurtz, Andrew J.
AU - Kanuri, Manorama
AU - Moriya, Masaaki
AU - Lloyd, R. Stephen
PY - 2003/8/1
Y1 - 2003/8/1
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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U2 - 10.1021/tx034066u
DO - 10.1021/tx034066u
M3 - Article
C2 - 12924930
AN - SCOPUS:0042878463
SN - 0893-228X
VL - 16
SP - 1019
EP - 1028
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 8
ER -