Multiple exocyclic DNA adducts arise from reactions of lipid and DNA peroxidation products with DNA bases. These endogenous lesions are mutagenic; therefore, monitoring adduct levels may provide a means of assessing genomic exposure to oxidative damage in human populations. The metabolic processing of endogenously formed exocyclic DNA adducts has now been investigated for the purpose of developing non-invasive markers of oxidative damage. The pyrimidopurinone deoxynucleoside adduct, M1dG, was found to undergo enzymatic oxidation to produce 6-oxo-M1dG. The corresponding base adduct, M1G, was subject to sequential oxidation producing first 6-oxo-M1G and then 2,6-dioxo-M1G. The enzymes xanthine oxidoreductase (XOR) and aldehyde oxidase (AO) catalyzed the oxidation of M1dG and M1G. Additionally, the unsubstitued etheno base adduct, 1,N2-etheno-Gua, and the substituted etheno base adduct, heptanone-1,N2-etheno-Gua, were oxidized to produce 2-oxo-etheno-Gua and 2-oxo-hepatanone-etheno-Gua, respectively; XOR catalyzed these oxidations. The deoxynucleoside adducts 1,N2-etheno-dG and 1,N6-etheno-dA were substrates for phosphorolysis to base adducts (1,N2-etheno-Gua and 1,N6-etheno-Ade) by purine nucleoside phosphorolase (PNP).
A body of evidence now exists that demonstrates exocyclic DNA adducts are subject to enzymatic oxidation and phosphorolysis reactions (sometimes in tandem). Exocyclic base adducts, with planar and unsaturated exocyclic rings, are the best substrates for enzymatic oxidation. Base adducts containing substitutions such as deoxyribose on the imidazole ring of M1dG and a heptanone chain on the etheno ring of heptanone-1,N2-etheno-Gua do not prohibit oxidative metabolism. The enzymes of purine catabolism (XOR, AO, and PNP) are also involved in the metabolic processing of exocyclic adducts. Based on in vivo metabolism studies at near-physiological concentrations of exogenously administered M1dG, the metabolic processing of exocyclic adducts is likely to occur at their physiological rate of production in animals and humans. In total, these results demonstrate that exocyclic adducts are subject to metabolic processing (oxidation and phosphorolysis). Furthermore, metabolites of endogenously produced DNA adducts are likely to be produced in vivo, and may provide a new class of biomarkers to assess exposure to endogenous sources DNA damage.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03122008-133135 |
| Date | 13 March 2008 |
| Creators | Knutson, Charles Gerhard Francesco |
| Contributors | Lawrence J. Marnett |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03122008-133135/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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