Oxidants generated by activated white blood cells are critical to host defenses against microorganisms. However, reactive species damage proteins and lipids and therefore might also damage host tissue. Moreover, they also oxidize nucleic acids and therefore could compromise the integrity of the genome. Such damage might account for the association between chronic inflammation and increased risk of cancer. The molecular mechanisms for oxidative damage of DNA during inflammation remain poorly understood, however. While addressing this issue, we identified three phagocyte-dependent pathways that oxidatively damage DNA in vitro: i) the myeloperoxidase pathway begins with activated neutrophils and monocytes, the cellular hallmarks of inflammation, ii) The reactive nitrogen pathway involves macrophages and/or endothelial cells, iii) The eosinophil peroxidase pathway operates in eosinophils, which are of central importance in host responses to parasitic infection. The overall goal of this proposal is to test the hypothesis that oxidants are generated by one or more of the above pathways during inflammation nitrate and halogenate nucleobases, promoting mutagenesis and damaging cells. We will seek evidence for the operation of the pathways through complementary studies of human and mouse tissue.
Our specific aims are: First, to determine whether tissue isolated from the lungs of smokers contains nucleobase oxidation products specific for the myeloperoxidase pathway, eosinophil peroxidase pathway, or reactive nitrogen pathway. Second, to use mouse models of chronic inflammation to investigate the roles of the myeloperoxidase pathway, reactive nitrogen pathway, and eosinophil peroxidase pathway in nucleobase oxidation in vivo. Third, to identify additional oxidized nucleobases generated by myeloperoxidase, reactive nitrogen species, or eosinophil peroxidase in vitro. These studies should provide insights into the molecular mechanisms of oxidative damage to DNA during inflammation.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Chemical Pathology Study Section (CPA)
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Finkelstein, David B
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Takeshita, Junko; Byun, Jaeman; Nhan, Thomas Q et al. (2006) Myeloperoxidase generates 5-chlorouracil in human atherosclerotic tissue: a potential pathway for somatic mutagenesis by macrophages. J Biol Chem 281:3096-104
Henderson, Jeffrey P; Byun, Jaeman; Takeshita, Junko et al. (2003) Phagocytes produce 5-chlorouracil and 5-bromouracil, two mutagenic products of myeloperoxidase, in human inflammatory tissue. J Biol Chem 278:23522-8
Byun, Jaeman; Henderson, Jeffrey P; Heinecke, Jay W (2003) Identification and quantification of mutagenic halogenated cytosines by gas chromatography, fast atom bombardment, and electrospray ionization tandem mass spectrometry. Anal Biochem 317:201-9
Yeh, George C; Henderson, Jeffrey P; Byun, Jaeman et al. (2003) 8-Nitroxanthine, a product of myeloperoxidase, peroxynitrite, and activated human neutrophils, enhances generation of superoxide by xanthine oxidase. Arch Biochem Biophys 418:1-12
Fu, Xiaoyun; Mueller, Dianne M; Heinecke, Jay W (2002) Generation of intramolecular and intermolecular sulfenamides, sulfinamides, and sulfonamides by hypochlorous acid: a potential pathway for oxidative cross-linking of low-density lipoprotein by myeloperoxidase. Biochemistry 41:1293-301
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Gaut, Joseph P; Byun, Jaeman; Tran, Hung D et al. (2002) Myeloperoxidase produces nitrating oxidants in vivo. J Clin Invest 109:1311-9
Gaut, J P; Yeh, G C; Tran, H D et al. (2001) Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis. Proc Natl Acad Sci U S A 98:11961-6
Kulcharyk, P A; Heinecke, J W (2001) Hypochlorous acid produced by the myeloperoxidase system of human phagocytes induces covalent cross-links between DNA and protein. Biochemistry 40:3648-56
Henderson, J P; Byun, J; Mueller, D M et al. (2001) The eosinophil peroxidase-hydrogen peroxide-bromide system of human eosinophils generates 5-bromouracil, a mutagenic thymine analogue. Biochemistry 40:2052-9

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