Endogenous Lipid Hydroperoxide-mediated DNA-adduct Formation in Min Mice

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. 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. Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Each year ∼130,000 people are diagnosed with colorectal cancer, and ∼56,000 will die from the disease. Multiple large epidemiological studies showed that regular use of NSAIDs 2The abbreviations used are: NSAID, non-steroidal anti-inflammatory drug; ϵdCyd, etheno-2′-deoxycytidine; CϵdCyd, carboxynonanone-ϵdCyd; ϵdGuo, etheno-2′-deoxyguanosine; CϵdGuo, carboxynonanone-ϵdGuo; COX, cyclooxygenase; EDE, 4,5-epoxy-2(E)-decenal; ϵdAdo, etheno-2′-deoxyadenosine; ESI, electrospray ionization; dGuo, 2′-deoxyguanosine; HϵdAdo, heptanone-ϵdAdo; HϵdCyd, heptanone-ϵdCyd; HϵdGuo, heptanone-etheno-dGuo; HNE, 4-hydroxy-2(E)-nonenal; HPETE, hydroperoxyeicosatetraenoic acid; HPNE, 4-hydroperoxy-2(E)-nonenal; LC, liquid chromatography; MS, mass spectrometry; M1G, pyrimido[1,2-a]purin-10(3H)one; MOPS, 3-morpholinopropanesulfonic acid; MRM, multiple reaction monitoring; ONE, 4-oxo-2(E)-nonenal; PG, prostaglandin. was associated with a reduction in the risk of cancer (1Waddell W.R. Gasner G.F. Cerise E.J. Loughry R.W. Am. J. Surg. 1989; 157: 175-178Abstract Full Text PDF PubMed Scopus (372) Google Scholar, 2Thun M.J. Gastroenterol. Clin. North Am. 1996; 25: 333-348Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Furthermore, for individuals with inherited familial adenomatous polyposis, NSAID intake was associated with a reduction in polyp number and size (1Waddell W.R. Gasner G.F. Cerise E.J. Loughry R.W. Am. J. Surg. 1989; 157: 175-178Abstract Full Text PDF PubMed Scopus (372) Google Scholar, 3Labayle D. Fischer D. Vielh P. Drouhin F. Pariente A. Bories C. Duhamel O. Trousset M. Attali P. Gastroenterology. 1991; 101: 635-639Abstract Full Text PDF PubMed Google Scholar, 4Giardiello F.M. Hamilton S.R. Krush A.J. Piantadosi S. Hylind L.M. Celano P. Booker S.V. Robinson C.R. Offerhaus G.J. N. Engl. J. Med. 1993; 328: 1313-1316Crossref PubMed Scopus (1563) Google Scholar). Likewise, NSAIDs have demonstrated their efficacy to inhibit carcinoma formation in animal models (5Pollard M. Luckert P.H. Science. 1981; 214: 558-559Crossref PubMed Scopus (161) Google Scholar, 6Mahmoud N.N. Dannenberg A.J. Mestre J. Bilinski R.T. Churchill M.R. Martucci C. Newmark H. Bertagnolli M.M. Surgery. 1998; 124: 225-231Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 7Sansom O.J. Stark L.A. Dunlop M.G. Clarke A.R. Cancer Res. 2001; 61: 7060-7064PubMed Google Scholar, 8Barnes C.J. Lee M. Gastroenterology. 1998; 114: 873-877Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The molecular mechanism for the ability of NSAIDs to inhibit tumor formation is not known. However, most NSAIDs inhibit both COX-1 and COX-2 (9Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2489) Google Scholar). The COX-1 enzyme, which is constitutively expressed in nearly all tissues in the body, predominantly plays a housekeeping role by mediating normal physiologic processes such as protection of the stomach and platelet aggregation (10Langenbach R. Morham S.G. Tiano H.F. Loftin C.D. Ghanayem B.I. Chulada P.C. Mahler J.F. Lee C.A. Goulding E.H. Kluckman K.D. Kim H.S. Smithies O. Cell. 1995; 83: 483-492Abstract Full Text PDF PubMed Scopus (1051) Google Scholar). The other isoform, COX-2, is inducible by various mitogens, growth factors, and mediators of inflammation in certain cells and tissues (11Williams C.S. DuBois R.N. Am. J. Physiol. 1996; 270: G393-G400PubMed Google Scholar). Although COX-1 is constitutively present in normal colon tissue, COX-2 levels are low to undetectable. In contrast, COX-2 mRNA is up-regulated in tumor tissue, and COX-2 protein is expressed in high amounts (12Eberhart C.E. Coffey R.J. Radhika A. Giardiello F.M. Ferrenbach S. DuBois R.N. Gastroenterology. 1994; 107: 1183-1188Abstract Full Text PDF PubMed Google Scholar). In rats that have been subjected to carcinogens, COX-2 mRNA and protein levels were increased in the tumors (13DuBois R.N. Radhika A. Reddy B.S. Entingh A.J. Gastroenterology. 1996; 110: 1259-1262Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar). Furthermore, cells overexpressing COX-2 have an altered cellular adhesion pathway, fail to undergo apoptosis, have increased invasiveness, and cell cycle prolongation (14Tsujii M. DuBois R.N. Cell. 1995; 83: 493-501Abstract Full Text PDF PubMed Scopus (2141) Google Scholar, 15DuBois R.N. Shao J. Tsujii M. Sheng H. Beauchamp R.D. Cancer Res. 1996; 56: 733-737PubMed Google Scholar, 16Tsujii M. Kawano S. DuBois R.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3336-3340Crossref PubMed Scopus (1331) Google Scholar). All of these changes were reversed by the addition of an NSAID, suggesting that COX-2-derived metabolites play an important role in tumorigenesis (14Tsujii M. DuBois R.N. Cell. 1995; 83: 493-501Abstract Full Text PDF PubMed Scopus (2141) Google Scholar, 15DuBois R.N. Shao J. Tsujii M. Sheng H. Beauchamp R.D. Cancer Res. 1996; 56: 733-737PubMed Google Scholar, 16Tsujii M. Kawano S. DuBois R.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3336-3340Crossref PubMed Scopus (1331) Google Scholar). In animal models, the absence of COX-2 expression inhibited polyp formation to 84% of control (17Chulada P.C. Thompson M.B. Mahler J.F. Doyle C.M. Gaul B.W. Lee C. Tiano H.F. Morham S.G. Smithies O. Langenbach R. Cancer Res. 2000; 60: 4705-4708PubMed Google Scholar), and overexpression of the COX-2 gene in transgenic mice was sufficient to induce polyp formation in >85% of the mice (18Liu C.H. Chang S.H. Narko K. Trifan O.C. Wu M.T. Smith E. Haudenschild C. Lane T.F. Hla T. J. Biol. Chem. 2001; 276: 18563-18569Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar). Arachidonic acid is the preferred substrate for COX-2. It catalyzes the bis-dioxygenation of arachidonic acid to form PGG2, a cyclic endoperoxide with a hydroperoxide at C-15. This is followed by reduction of the C15-hydroperoxide to give PGH2 (the peroxidase reaction). PGH2 is the precursor to the formation of thromboxane A2, prostacyclin, and other PGs (9Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2489) Google Scholar, 19Vane J.R. Bakhle Y.S. Botting R.M. Annu. Rev. Pharmacol. Toxicol. 1998; 38: 97-120Crossref PubMed Scopus (2638) Google Scholar). When mice were fed eicosapentaenoic acid, an ω-3 fatty acid, this resulted in a significant reduction in intestinal arachidonic acid content and PGE2 levels as well as a 64% reduction in polyp load (20Petrik M.B. McEntee M.F. Chiu C.H. Whelan J. J. Nutr. 2000; 130: 1153-1158Crossref PubMed Scopus (72) Google Scholar). In addition, when cytosolic phospholipase 2, a phospholipase that has been well characterized as a major arachidonic acid releasing enzyme, was deleted in Min mice, there was an 83% reduction in polyp number (21Hong K.H. Bonventre J.C. O'Leary E. Bonventre J.V. Lander E.S. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3935-3939Crossref PubMed Scopus (125) Google Scholar). The ability to inhibit polyp formation by NSAIDs and the reduction of arachidonic acid availability suggested that eicosanoid production may be very important in promoting carcinogenesis. In addition, eicosanoids have the ability to modulate various steps involved in carcinogenesis such as apoptosis and angiogenesis. However, eicosanoids are also produced by COX-1, which is present in both affected and unaffected tissue. This suggests that there may be a link between polyp formation and COX-2 up-regulation through a pathway that does not involve the biosynthesis of eicosanoids. COX-2 can convert arachidonic acid into 15-hydroxy-5,8,11,13-(Z,Z,Z,E)-eicosatetraenoic acid (15-HETE) (22Lee S.H. Oe T. Blair I.A. Science. 2001; 292: 2083-2086Crossref PubMed Scopus (405) Google Scholar), which is derived from 15-HPETE, a prototypic ω-6 polyunsaturated fatty acid-derived lipid hydroperoxide. In settings of oxidative stress, where reducing pathways were compromised, 15-HPETE may survive long enough to induce DNA damage. Recently, it was demonstrated that 15-HPETE underwent homolytic decomposition to form DNA-reactive bifunctional electrophiles, HPNE, HNE, ONE, and EDE (23Williams M.V. Lee S.H. Blair I.A. Rapid Commun. Mass Spectrom. 2005; 19: 849-858Crossref PubMed Scopus (30) Google Scholar). Two distinct pathways of decomposition were identified. The first involved the intermediate formation of HPNE, and the second involved a series of complex rearrangements to EDE (24Pryor W.A. Porter N.A. Free Radic. Biol. Med. 1990; 8: 541-543Crossref PubMed Scopus (196) Google Scholar, 25Lee S.H. Oe T. Blair I.A. Chem. Res. Toxicol. 2002; 15: 300-304Crossref PubMed Scopus (74) Google Scholar). HPNE was shown to be the immediate precursor of ONE and HNE (22Lee S.H. Oe T. Blair I.A. Science. 2001; 292: 2083-2086Crossref PubMed Scopus (405) Google Scholar, 23Williams M.V. Lee S.H. Blair I.A. Rapid Commun. Mass Spectrom. 2005; 19: 849-858Crossref PubMed Scopus (30) Google Scholar, 26Jian W. Lee S.H. Arora J.S. Elipe M.V. Silva Blair I.A. Chem. Res. Toxicol. 2005; 18: 599-610Crossref PubMed Scopus (25) Google Scholar, 27Schneider C. Tallman K.A. Porter N.A. Brash A.R. J. Biol. Chem. 2001; 276: 20831-20838Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar, 28Lee S.H. Blair I.A. Chem. Res. Toxicol. 2000; 13: 698-702Crossref PubMed Scopus (232) Google Scholar). It was recently demonstrated that HPNE also formed adducts with DNA S.H. Arora Oe T. Blair I.A. Chem. Res. Toxicol. 2005; 18: PubMed Scopus Google Scholar). EDE also formed adducts S.H. Oe T. Blair I.A. Chem. Res. Toxicol. 2002; 15: 300-304Crossref PubMed Scopus (74) Google Scholar), and ONE formed heptanone-etheno adducts D. Lee S.H. M. Blair I.A. Chem. Res. Toxicol. 2000; 13: PubMed Scopus Google Scholar, D. M. S. K. Blair I.A. Chem. Res. Toxicol. PubMed Scopus (138) Google Scholar, M. Oe T. Lee S.H. Elipe M.V. Silva Blair I.A. Chem. Res. Toxicol. PubMed Scopus Google However, HPNE was in the formation of adducts EDE, suggesting that it is the for the formation of these adducts S.H. Arora Oe T. Blair I.A. Chem. Res. Toxicol. 2005; 18: PubMed Scopus Google Scholar). adducts are highly in mammalian cells and have been detected in DNA M. M. Cancer Res. 2000; 60: Google Scholar, S. Chem. Res. Toxicol. PubMed Scopus Google Scholar). Recently, we showed that the heptanone-etheno HϵdCyd, was highly in both and H. C. F. A. and M. for there were in and between and H. C. F. A. and M. for In studies we showed that the decomposition of lipid to DNA-reactive bifunctional This made it to an in to that DNA in rat intestinal epithelial cells stably COX-2. was a in formation in the of in these cells S.H. M.V. DuBois R.N. Blair I.A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). formation with biosynthesis was inhibited by a specific COX-2 S.H. M.V. DuBois R.N. Blair I.A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Therefore, there is that DNA may play a role in Min mice are of the most used mouse models for colorectal mice large of In addition, up-regulation of COX-2 in the in these mice has been well characterized C.S. C. Radhika A. T. Beauchamp R.D. DuBois R.N. Gastroenterology. 1996; Full Text PDF PubMed Scopus Google Scholar). Therefore, this mouse model and were used to heptanone-etheno adducts were present in the DNA. A quantitative stable isotope dilution was used to heptanone-etheno adducts in the intestinal tissue. and and were from was from liquid and were from and were from DNA with by in was by were by and C57BL/6JAPCmin mice were as from of were fed and by The was and at for DNA Mass for the quantitative of DNA adducts was with a with an in the was used for the and at and was as the at in the second was to the of the second at to enough to the that to form at was for both precursor and The were for quantitative DNA was on a with a The a A was and was The was as at at at at at at and at The was The was at for DNA adducts on was a The a A was in and was in The was as at at at at at at at at The was The was at of DNA from from the of mice was a DNA tissue was in and with an reaction and to the DNA from the This was followed by and steps to the DNA. of DNA were It was as and normal were by of DNA and of DNA DNA was and in (22Lee S.H. Oe T. Blair I.A. Science. 2001; 292: 2083-2086Crossref PubMed Scopus (405) Google in was and at for the of the the was to by was and was for a at was followed by in and was for at were through a this an was for of the of DNA was by of of The was to a that been with and The was with and a were with an The were to of adducts were in were by The were to the was from by the of amounts of and the were for the molecular of the endogenous and for that were to the of the from the endogenous and levels were to the of DNA as detected by and from Min mice were with DNA The of DNA in was as and DNA were from the in the of and DNA adducts were by as The were by the from HϵdGuo, from HϵdAdo, from of with in (22Lee S.H. Oe T. Blair I.A. Science. 2001; 292: 2083-2086Crossref PubMed Scopus (405) Google was with in the of DNA for at The reaction was on for DNA was by and It was as and normal were by of DNA for and CϵdGuo, CϵdCyd, HϵdAdo, HϵdCyd, and derived from of a and their isotope are shown in and were for in the of to and control were A for CϵdCyd, HϵdAdo, HϵdCyd, HϵdGuo, and was and of DNA-adduct with are for and of C57BL/6J was from the of C57BL/6J mice. The DNA was subjected to in the of A of was for the of normal which was used to the of DNA in the The endogenous DNA adducts were from the in the was A for the C57BL/6J mouse DNA adducts and their is shown in and The DNA adducts were a and by the of DNA that was from the The number of adducts detected for the C57BL/6J mice is normal and normal and of from the of a C57BL/6J are for and normal formed in the of the control mice and C57BL/6JAPCmin mice The was a in a DNA normal formed in the of the control C57BL/6J mice and C57BL/6JAPCmin mice. were with an Each of the and the in the of the of C57BL/6JAPCmin the DNA was from the of the C57BL/6JAPCmin mice and DNA adducts were and by and The number of adducts detected for the C57BL/6JAPCmin mice are normal and normal and of from the of a Min are for and and of DNA formation of heptanone-etheno-DNA adducts was by DNA to the tissue DNA was DNA was from the tissue and the normal HϵdGuo, HϵdAdo, and were to the DNA of the heptanone-etheno adducts were all of the This showed that no formation In contrast, the amounts of endogenous and were the of endogenous was the of of the DNA in was in the of and DNA. was for the of the adducts The most adducts formed were the heptanone-etheno normal normal was the most and normal was the adducts were detected the last two there has been a to lipid hydroperoxide-derived endogenous DNA adducts as for Using highly specific and sensitive stable isotope dilution methodology in with by it has been to ϵdGuo, ϵdAdo, ϵdCyd, and the in mammalian tissue DNA we showed that the adducts most arise from HPNE, the of homolytic lipid hydroperoxide decomposition S.H. 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Cancer Res. 2000; 60: Google Scholar). adducts arise from the of Furthermore, we have recently demonstrated that is highly in both mammalian and Therefore, heptanone-etheno adducts as specific of endogenous lipid hydroperoxide-mediated DNA damage. Using the Min mouse model of colon cancer, we have demonstrated that heptanone-etheno adducts are present in both affected and unaffected colon tissue. DNA was from the of C57BL/6J and C57BL/6JAPCmin mice and in the of The was to the in the of (17Chulada P.C. Thompson M.B. Mahler J.F. Doyle C.M. Gaul B.W. Lee C. Tiano H.F. Morham S.G. Smithies O. Langenbach R. Cancer Res. 2000; 60: 4705-4708PubMed Google Scholar). was to and was stable isotope dilution In it was shown that the adducts were not as an the and of the DNA. A for the DNA adducts and their stable isotope is shown in and A quantitative comparison of formation in C57BL/6J and C57BL/6JAPCmin mice DNA was were statistically significant increased levels of the adducts that we were to in the C57BL/6JAPCmin mice the C57BL/6J mice and with cell S.H. M.V. DuBois R.N. Blair I.A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), that increased levels of COX-2, as is the in the of the C57BL/6JAPCmin mice C.S. C. Radhika A. T. Beauchamp R.D. DuBois R.N. Gastroenterology. 1996; Full Text PDF PubMed Scopus Google Scholar), in increased levels of the was increased from normal to was also increased from normal to normal The for and were in the of and to the of the it to adducts that may have been present and levels were to the of the and However, there to be a an in the Min mice. that the and adducts may be markers for the of colorectal The major adducts in DNA with were the heptanone-etheno was found at levels of normal was as with normal and was by the with only normal The adducts were the heptanone-etheno adducts not adducts were This was to form the acid precursor to form the When DNA adducts in DNA the mouse tissue, there was a in the most adducts This suggests that there are for these adducts and that the certain was the most in tissue may be as a cell and tissue and were the suggesting that were Therefore, are for In we have detected the endogenous formation of heptanone-etheno DNA adducts for the first in mammalian tissue. Using highly specific and sensitive it was to the of adducts present in the colon tissue of normal C57BL/6J mice and C57BL/6JAPCmin mice, a colorectal cancer were statistically significant increased levels of adducts in the Min mice when compared with the mice. This suggests that heptanone-etheno adducts in colon tissue DNA may as a of increased risk for colorectal Furthermore, there was a in the adducts formed between an in and the in vivo mouse which suggests that DNA may certain DNA The adducts that are may be in the of these adducts may of endogenous lipid DNA in a similar to the well characterized DNA adducts of that have well as of DNA A. Res. PubMed Scopus Google Scholar). We of for the of C57BL/6J and C57BL/6JAPCmin mice and of the of for We also for the of a mass with

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