Genotoxic Mechanism for the Major Acrolein-Derived Deoxyguanosine Adduct in Human Cells

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Abstract
Acrolein, widely distributed in the environment and also produced endogenously, forms deoxyguanosine adducts in DNA. The genotoxicity of the major acrolein-dG adduct, 8α and 8β isomers of 3H-8-hydroxy-3-(β-d-2‘-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one (γ-OH-PdG), and the model adduct, PdG, which lacks the hydroxy group of γ-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 γ-OH-PdG and 25% for PdG when compared with dG control. γ-OH-PdG was marginally miscoding (≤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 γ-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, γ-OH-PdG, is less blocking to DNA synthesis and less miscoding than the model adduct, PdG.

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