Endogenous lipid hydroperoxide-mediated DNA-adduct formation in min mice
| Autor: | Michelle V. Williams, Seaon Hwa Lee, Michael Pollack, Ian A. Blair |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Lipid Peroxides
Spectrometry Mass Electrospray Ionization DNA damage Transgene Endogeny Mice Transgenic Tandem mass spectrometry Biochemistry Gene Expression Regulation Enzymologic Mass Spectrometry Adduct chemistry.chemical_compound DNA Adducts Mice In vivo Cell Line Tumor Animals Humans Molecular Biology Chemistry Epithelial Cells Cell Biology DNA Mice Inbred C57BL Models Chemical Cell culture Cyclooxygenase 2 Colorectal Neoplasms Chromatography Liquid DNA Damage |
| Zdroj: | The Journal of biological chemistry. 281(15) |
| ISSN: | 0021-9258 |
| Popis: | Despite intensive research over the last two decades, there are still no specific markers of endogenous lipid hydroperoxide-mediated DNA damage. We recently demonstrated that heptanone-etheno-2'-deoxyguanosine adducts are formed in the DNA of rat intestinal epithelial cells that stably express cyclooxygenase-2. Heptanone-etheno adducts can only arise from the reaction of lipid hydroperoxide-derived 4-oxo-2(E)-nonenal with DNA. This raised the possibility that similar adducts would be formed in vivo in settings where cyclooxygenase-2 expression is increased. Therefore, DNA-adduct formation was studied in C57BL/6JAPC(min) mice, a colorectal cancer mouse model in which cyclooxygenase-2 is up-regulated. 15(S)-Hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid is the major lipid hydroperoxide produced endogenously by cyclooxygenase-2. It undergoes homolytic decomposition to the DNA-reactive bifunctional electrophile 4-oxo-2(E)-nonenal, which forms heptanone-etheno adducts with DNA. A quantitative comparison was made of the heptanone-etheno-DNA adducts present in C57BL/6J and C57BL/6JAPC(min) mice. Using highly specific and sensitive methodology based on stable isotope dilution liquid chromatography/tandem mass spectrometry, we have detected the endogenous formation of heptanone-etheno adducts in mammalian tissue DNA for the first time. In addition, we found that there were statistically significant increased levels of the heptanone-etheno-2'-deoxyguanosine and heptanone-etheno-2'-deoxycytidine adducts in the C57BL/6JAPC(min) mice when compared with the control C57BL/6J mice. |
| Databáze: | OpenAIRE |
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