Covalent Modifications to 2‘-Deoxyguanosine by 4-Oxo-2-nonenal, a Novel Product of Lipid Peroxidation

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Abstract
Two major products (adducts A and B) from the reaction of 2‘-deoxyguanosine (dGuo) with 13-hydroperoxylinoleic acid were detected by liquid chromatography/mass spectrometry (LC/MS). Adducts A and B were also the major products formed enzymatically when dGuo was incubated in the presence of linoleic acid and lipoxygenase. The mass spectral fragmentation patterns of adducts A and B suggested that unique modifications to the nucleoside had been introduced. This resulted in the characterization of a novel bifunctional electrophile, 4-oxo-2-nonenal, as the principal breakdown product of linoleic acid hydroperoxide. In subsequent studies, adduct A was found to be a substituted ethano dGuo adduct that was a mixture of three isomers (A1−A3) that all decomposed to form adduct B. Adduct A1 was the hemiacetal form of 3-(2‘-deoxy-β-d-erythropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(heptane-2‘ ‘-one)-9H-imidazo[1,2-α]purine-9-one. Adducts A2 and A3 were the diastereomers of the open chain ketone form. Adduct B was the substituted etheno dGuo adduct, 3-(2‘-deoxy-β-d-erythropentafuranosyl)imidazo-7-(heptane-2‘ ‘-one)-9-hydroxy[1,2-α]purine, the dehydration product of adducts A1−A3. Identical covalent modifications to dGuo were observed when calf-thymus DNA was treated with 4-oxo-2-nonenal. These data illustrate the diversity of reactive electrophiles produced from the peroxidative decomposition of lipids and have implications in fully assessing the role of lipid peroxidation in mutagenesis and carcinogenesis.

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