Purine DNA adducts of 4,5-dioxovaleric acid and 2,4-decadienal.
The present overview describes recent findings on the formation of cyclic adducts of purine DNA bases after reaction with two aldehyde compounds, 4,5-dioxovaleric acid (DOVA) and 2,4-decadlenal (DDE), which are involved in 5-aminolaevulinic acid (ALA) accumulation and lipid peroxidation, respectively. ALA accumulates under pathological conditions and is associated with an increased incidence of liver cancer. The final oxidation product of ALA, DOVA, is an efficient alkylating agent of the guanine moieties in both nucleoside and isolated DNA. Adducts were produced through the formation of a Schiff base involving the N2-amino group of 2'-deoxyguanosine and the ketone function of DOVA, respectively. DDE is an important breakdown product of lipid peroxidation. It is cytotoxic to mammalian cells and is known to be implicated in DNA damage. It can bind to 2'-deoxyadenosine, yielding highly fluorescent products, including 1,N6-etheno-2'-deoxyadenosine and two other, related adducts. The reaction mechanism for the formation of DDE-2'-deoxyadenosine adducts involves epoxidation of DDE and subsequent addition of the resulting reactive intermediates to the N6 amino group of 2'-deoxyadenosine, followed by cyclization at the N1 site. Formation of endogenous DNA adducts may contribute to the genotoxic potential of ALA and DDE.
Cadet
J
J
Département de Recherche Fondamentale sur la Matière Condensée Laboratoire 'Lésions des Acides Nucléiques, Grenoble, France.
Carvalho
V M
VM
Onuki
J
J
Douki
T
T
Medeiros
M H
MH
Di Mascio
P D
PD
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000478:Alkylation; D000818:Animals; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry; D003849:Deoxyguanosine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008956:Models, Chemical; D051381:Rats; D014631:Valerates / Q000737:chemistry / Q000378:metabolism*
D000447:Aldehydes; D018736:DNA Adducts; D014631:Valerates; C057349:2,4-decadienal; C007509:4,5-dioxovaleric acid; D003849:Deoxyguanosine