Endogenous lipid hydroperoxide-mediated DNA-adduct formation in min mice

Michelle V. Williams, Hwa Lee Seon, Michael Pollack, Ian A. Blair

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

Abstract

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/6JAPCmin 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/6JAPCmin 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/6JAPCmin mice when compared with the control C57BL/6J mice.

Original languageEnglish
Pages (from-to)10127-10133
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number15
DOIs
Publication statusPublished - 2006 Apr 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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