Genotoxic mechanism for the major acrolein-derived deoxyguanosine adduct in human cells.
Acrolein, widely distributed in the environment and also produced endogenously, forms deoxyguanosine adducts in DNA. The genotoxicity of the major acrolein-dG adduct, 8alpha and 8beta isomers of 3H-8-hydroxy-3-(beta-D-2'-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one (gamma-OH-PdG), and the model adduct, PdG, which lacks the hydroxy group of gamma-OH-PdG, was investigated in human cells. The adducts were site-specifically incorporated into a SV40/BK origin-based shuttle vector. Estimated efficiencies of translesion DNA synthesis were 73% for gamma-OH-PdG and 25% for PdG when compared with dG control. Gamma-OH-PdG was marginally miscoding (<or=1%), inducing G-->T and G-->A base substitutions in HeLa and xeroderma pigmentosum complementation group A (XP-A) and variant (XP-V) cells. There was no significant difference in the miscoding frequency when the adduct was inserted in the leading or lagging strand. PdG was more miscoding than gamma-OH-PdG by inducing targeted base substitutions (G-->T, A, or C) at a frequency of 7.5% in XP-A cells. Thus, the authentic major adduct, gamma-OH-PdG, is less blocking to DNA synthesis and less miscoding than the model adduct, PdG.
Yang
In-Young
IY
Laboratory of Chemical Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
Johnson
Francis
F
Grollman
Arthur P
AP
Moriya
Masaaki
M
D000171:Acrolein / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009153:Mutagens / Q000378:metabolism / Q000494:pharmacology*
D018736:DNA Adducts; D009153:Mutagens; C424742:OH-1,-N(2)-propano-2'-deoxyguanosine; C060934:1,N(2)-propanodeoxyguanosine; D000171:Acrolein; D003849:Deoxyguanosine