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

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• 作者：Diane Rindgen ; Masaharu Nakajima ; Suzanne Wehrli ; Keyang Xu ; and Ian A. Blair
• 刊名：Chemical Research in Toxicology
• 出版年：1999
• 出版时间：December 1999
• 年：1999
• 卷：12
• 期：12
• 页码：1195 - 1204
• 全文大小：213K
• 年卷期：v.12,no.12(December 1999)
• ISSN：1520-5010

文摘

Two major products (adducts A and B) from the reaction of 2'-deoxyguanosine (dGuo) with13-hydroperoxylinoleic acid were detected by liquid chromatography/mass spectrometry (LC/MS). Adducts A and B were also the major products formed enzymatically when dGuo wasincubated in the presence of linoleic acid and lipoxygenase. The mass spectral fragmentationpatterns of adducts A and B suggested that unique modifications to the nucleoside had beenintroduced. This resulted in the characterization of a novel bifunctional electrophile, 4-oxo-2-nonenal, as the principal breakdown product of linoleic acid hydroperoxide. In subsequentstudies, adduct A was found to be a substituted ethano dGuo adduct that was a mixture ofthree isomers (A₁-A₃) that all decomposed to form adduct B. Adduct A₁ was the hemiacetalform of 3-(2'-deoxy--D-erythropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(heptane-2' '-one)-9H-imidazo[1,2-]purine-9-one. Adducts A₂ and A₃ were the diastereomers of the open chainketone form. Adduct B was the substituted etheno dGuo adduct, 3-(2'-deoxy--D-erythropentafuranosyl)imidazo-7-(heptane-2' '-one)-9-hydroxy[1,2-]purine, the dehydration product ofadducts A₁-A₃. Identical covalent modifications to dGuo were observed when calf-thymus DNAwas treated with 4-oxo-2-nonenal. These data illustrate the diversity of reactive electrophilesproduced from the peroxidative decomposition of lipids and have implications in fully assessingthe role of lipid peroxidation in mutagenesis and carcinogenesis.