Unexpected formation of etheno-2′-deoxyguanosine adducts from 5(S)-hydroperoxyeicosatetraenoic acid: Evidence for a bis-hydroperoxide intermediate

Wenying Jian, Seon Hwa Lee, Jasbir S. Arora, Maria V.Silva Elipe, Ian A. Blair

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25 Citations (Scopus)


Analysis of products from the reaction between 5(S)-hydroperoxy-6,8,11,14- (E,Z,Z,Z)-eicosatetraenoic acid and 2′-deoxyguanosine in the presence of FeII, FeIII, or vitamin C by liquid chromatography/ atmospheric pressure chemical ionization/mass spectrometry revealed the presence of four DNA adducts. Surprisingly, adducts I and II had mass spectral characteristics identical to those for 1,N2-etheno-2′- deoxyguanosine and heptanone-1,N2-etheno-2′-deoxyguanosine. These adducts have previously been shown to arise from the homolytic decomposition of 13(S)-hydroperoxy-9,11-(Z,E)-octadecadienoic acid. It appears that under the reaction conditions, 5(S)-hydroperoxy-6,8,11,14-(E,Z,Z,Z)- eicosatetraenoic acid was subjected to a previously unknown peroxidation reaction to give a bis-hydroperoxide intermediate that underwent a Hock rearrangement to produce 3(Z)-nonenal from the ω-terminus. The 3(Z)-nonenal was then converted to 4-hydroperoxy-2-nonenal, a precursor to the formation of 4-oxo-2-nonenal. 4-Oxo-2-nonenal forms heptanone-1,N 2-etheno-adducts with 2′-deoxyguanosine, whereas 4-hydroperoxy-2-nonenal forms 1,N2-etheno-2′-deoxyguanosine. Two novel carboxylate adducts were also identified. The structure of the more abundant adduct (III) was characterized as its methyl ester derivative by NMR spectroscopy as 3-(2′-deoxy-β-D-erythropentafuranosyl)-imidazo-7- (5″-carboxypenta-2″-one)-9-oxo[1,2-α]purine(5-carboxy-2- pentanone-1,N2-etheno-2′-deoxyguanosine). This etheno adduct was formed by the reaction of 2′-deoxyguanosine with 5,8-dioxo-6(E)- octenoic acid. The bifunctional electrophile is proposed to arise from the α-terminus during the Hock rearrangement of bis-hydroperoxide derived from 5(S)-hydroperoxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid. 5-Carboxy-2-pentanone-1,N2-etheno-2′-deoxyguanosine may serve as a biomarker of 5-lipoxygenase-mediated oxidative stress. The less abundant carboxylate adduct IV arose from a quite different pathway and was tentatively characterized as 6-carboxy-3-hydroxy-1-hexene-1,N2-etheno-2′- deoxyguanosine.

Original languageEnglish
Pages (from-to)599-610
Number of pages12
JournalChemical Research in Toxicology
Issue number3
Publication statusPublished - 2005 Mar 1


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