1. In vivo detection of a novel endogenous etheno-DNA adduct derived from arachidonic acid and the effects of antioxidants on its formation.
- Author
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Fu Y, Nath RG, Dyba M, Cruz IM, Pondicherry SR, Fernandez A, Schultz CL, Yang P, Pan J, Desai D, Krzeminski J, Amin S, Christov PP, Hara Y, and Chung FL
- Subjects
- Adenosine analysis, Adenosine biosynthesis, Animals, Antioxidants chemistry, Arachidonic Acid chemistry, Catechin analogs & derivatives, Catechin pharmacology, Chromatography, Liquid, DNA Adducts analysis, DNA Adducts chemistry, Deoxyadenosines analysis, Deoxyadenosines chemistry, Deoxyguanosine biosynthesis, Epoxy Compounds chemistry, Humans, Liver metabolism, Rats, Rats, Inbred F344, Rats, Inbred LEC, Rats, Sprague-Dawley, Spectrometry, Mass, Electrospray Ionization, Thioctic Acid pharmacology, Vitamin E pharmacology, Adenosine analogs & derivatives, Antioxidants pharmacology, DNA Adducts biosynthesis, Deoxyadenosines biosynthesis, Deoxyguanosine analogs & derivatives
- Abstract
Previous studies showed that 7-(1',2'-dihydroxyheptyl)-substituted etheno DNA adducts are products of reactions with the epoxide of (E)-4-hydroxy-2-nonenal, an oxidation product of ω-6 polyunsaturated fatty acids (PUFAs). In this work, we report the detection of 7-(1',2'-dihydroxyheptyl)-1,N(6)-ethenodeoxyadenosine (DHHedA) in rodent and human tissues by two independent methods: a (32)P-postlabeling/HPLC method and an isotope dilution liquid chromatography-electrospray ionization-tandem mass spectrometry method, demonstrating for the first time that DHHedA is a background DNA lesion in vivo. We showed that DHHedA can be formed upon incubation of arachidonic acid with deoxyadenosine, supporting the notion that ω-6 PUFAs are the endogenous source of DHHedA formation. Because cyclic adducts are derived from the oxidation of PUFAs, we subsequently examined the effects of antioxidants, α-lipoic acid, Polyphenon E, and vitamin E, on the formation of DHHedA and γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG), a widely studied acrolein-derived adduct arising from oxidized PUFAs, in the livers of Long Evans Cinnamon (LEC) rats. LEC rats are afflicted with elevated lipid peroxidation and prone to the development of hepatocellular carcinomas. The results showed that although the survival of LEC rats was increased significantly by α-lipoic acid, none of the antioxidants inhibited the formation of DHHedA, and only Polyphenon E decreased the formation of γ-OHPdG. In contrast, vitamin E caused a significant increase in the formation of both γ-OHPdG and DHHedA in the livers of LEC rats., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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