trans,trans-2,4-decadienal-induced 1,N(2)-etheno-2'-deoxyguanosine adduct formation.
A number of ring-extended DNA adducts resulting from the reaction of alpha,beta-unsaturated aldehydes, or their epoxides, with DNA bases have been characterized in recent years. These adducts may lead to miscoding during DNA replication, resulting, if not repaired, in mutations that can contribute to cancer development. trans,trans-2, 4-Decadienal (DDE) is one of the highly cytotoxic aldehydes endogenously formed from lipid peroxidation. To evaluate its DNA damaging potential, we have investigated the reaction of DDE with 2'-deoxyguanosine (dGuo) in the presence of peroxides. Three stable adducts were isolated by reverse-phase HPLC. Adduct A1, 3-(2-deoxy-beta-D-erythro-pentafuranosyl)-5,9-dihydro-9H-imidazo[2 , 1-i]purin-9-hydroxy, is a tautomer of 1, N(2)-etheno-2'-deoxyguanosine, a well-known reaction product of epoxy aldehydes with dGuo. Two new diasteroisomeric products, A2-1 and A2-2, 1-¿[3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-5, 9-dihydro-9H-imidazo[2,1-i]purin-9-hydroxy]-7-yl¿-2-one-3-octanol, were isolated and characterized on the basis of their spectroscopic features as 1,N(2)-etheno adducts possessing a carbon side chain with a carbonyl and a hydroxyl group. The proposed reaction mechanism for the formation of adducts A2 involves DDE double epoxidation and hydrolysis of the C4 epoxy group prior to nucleophilic addition of the exocyclic amino group of dGuo to C1 of the aldehyde, followed by cyclization via nucleophilic attack on the C2 epoxy group by N-1 and elimination of H(2)O. After treatment of calf thymus DNA with DDE, formation of adducts A1 and A2 was detected by the LC/ESI/MS-MS technique. These results can contribute to a better understanding of the chemical structures of adducts resulting from the reaction of aldehydes with nucleic acid bases, a necessary step in assessing the genotoxic risks associated with this class of compounds.
Loureiro
A P
AP
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Brazil.
Di Mascio
P
P
Gomes
O F
OF
Medeiros
M H
MH
D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D013950:Thymus Gland / Q000737:chemistry
D000447:Aldehydes; D018736:DNA Adducts; C054579:1,N(2)-ethenodeoxyguanosine; C057349:2,4-decadienal; D004247:DNA; D003849:Deoxyguanosine