DNA Modifications by the ω-3 Lipid Peroxidation-Derived Mutagen 4-Oxo-2-hexenal in Vitro and Their Analysis in Mouse and Human DNA

Abstract

4-Oxo-2-hexenal (4-OHE), which forms a 2'-deoxyguanosine (dG) adduct in a model lipid peroxidation system, is mutagenic in the Ames test. It is generated by the oxidation of omega-3 fatty acids and is commonly found in dietary fats, such as fish oil, perilla oil, rapeseed oil, and soybean oil. 4-OHE also forms adducts with 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), and 5-methyl-2'-deoxycytidine (5-Me-dC) in DNA. In this study, we characterized the structures of these adducts in detail. We measured the amounts of 4-OHE-DNA adducts in mouse organs by LC/MS/MS, after 4-OHE was orally administered to mice. The 4-OHE-dA, 4-OHE-dC, 4-OHE-dG, and 4-OHE-5-Me-dC adducts were detected in stomach and intestinal DNA in the range of 0.25-43.71/10(8) bases. After the 4-OHE administration, the amounts of these DNA adducts decreased gradually over 7 days. We also detected 4-OHE-dC in human lung DNA, in the range of 2.6-5.9/10(9) bases. No difference in the 4-OHE adduct levels was detected between smokers and nonsmokers. Our results suggest that 4-OHE-DNA adducts are formed by endogenous as well as environmental lipid peroxides.

Detection of Lipid Peroxidation-Induced DNA Adducts Caused by 4-Oxo-2(E)-nonenal and 4-Oxo-2(E)-hexenal in Human Autopsy Tissues

“…1 Abbreviations: PUFA, polyunsaturated fatty acid; LPO, lipid peroxidation; 4-HNE, 4-hydroxy-2(E)-nonenal; 4-ONE, 4-oxo-2(E)-nonenal; 4-OHE, 4-oxo-2(E)-hexenal; HεdC, heptanone-etheno-2′-deoxycytidine; HεdG, heptanone-etheno-2′-deoxyguanosine; HεdA, heptanone-etheno-2′deoxyadenosine; BεdC, butanone-etheno-2′-deoxycytidine; BεmedC, butanone-etheno-2′-deoxy-5-methylcytidine; BεdG, butanone-etheno-2′-deoxyguanosine; BεdA, butanone-etheno-2′-deoxyadenosine; 8-oxodG, 8-oxo-7,8-dihydro-2′-deoxyguanosine; εdA, 1,N 6 -etheno-2′-deoxyadenosine; 8-OH-AdG, 8-hydroxy-1,N 2 -propanodeoxyguanosine; CdG 2 , R-R-methyl-γhydroxy-1,N 2 -propano-2′-deoxyguanosine;COX-2, cyclooxygenase-2; HPNE, 4-hydroperoxy-2(E)-nonenal; EDE, 4,5-epoxy-2(E)-decenal; 5-LO, 5-lipoxygenase. such as butanone-etheno-2′-deoxycytidine (BεdC), butanoneetheno-2′-deoxy-5-methyl-cytidine (BεmedC), butanone-etheno-2′-deoxyguanosine (BεdG) (19)(20)(21), and butanone-etheno-2′deoxyadenosine (BεdA) (22). The levels of 4-ONE-and 4-OHErelated DNA adducts in humans are currently unknown because such adducts were discovered only very recently.…”

Identification of Octenal-Related dA and dC Adducts Formed by Reactions with a Hemin-ω-6-fat Peroxidation Model System

“…HMQC NMR spectrum of dA* is shown in FigureS2(Supporting Information). The 1-hydroxy-hexyl side chain was attached to C-11 of the imidazole ring, as confirmed by the cross-peaks observed between H-1″ and N-1 by 1 H-15 N HMBC.…”

“…In an animal experiment, higher levels of etheno-type dC and dA adducts were detected in the colon epithelium DNA after the administration of linoleic acid . Various adducts, such as etheno-type-dC, -dA, and -dG adducts, 1, N 2 -propano-type dG adducts, and a malonaldehyde DNA adduct, induced by the lipid peroxidation products, have been measured in animal and human tissues. − Chou et al reported that 4-ONE-dA and -dC are the major types of adducts detected in human autopsy tissues . Lipid peroxide-derived DNA adducts were also detected in human gastric mucosa .…”

Application of DNA adductomics to soil bacterium Sphingobium sp. strain KK22

“…Among known DNA adducts that may correspond to [M + H] + = 346, the 2′-deoxynucleoside of butanone-ethenoadenine is a lipid peroxidation-derived lesion that has been detected in vivo and has a molar mass of 345 g mol −1 (Kawai et al. 2010 ). Because the retention time of putative adduct d was nearly the same as the adduct identified as 8-hydroxy-PdG (Table 2 ) it was annotated as either a sodiated adduct of 8-hydroxy-PdG or as a possible butanone-ethenoadenine adduct.…”