title: Endogenous lipid hydroperoxide-mediated DNA-adduct formation in min mice.
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/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.
authors.affiliation: Center for Cancer Pharmacology, University of Pennsylvania, 854 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors.forename: Michelle V
authors.initials: MV
authors.lastname: Williams
authors.forename: Seon Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Pollack
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008054:Lipid Peroxides / Q000737:chemistry* / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008956:Models, Chemical; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D018736:DNA Adducts; D008054:Lipid Peroxides; D004247:DNA; D051546:Cyclooxygenase 2