title: Myeloperoxidase-induced genomic DNA-centered radicals.
abstract: Myeloperoxidase (MPO) released by activated neutrophils can initiate and promote carcinogenesis. MPO produces hypochlorous acid (HOCl) that oxidizes the genomic DNA in inflammatory cells as well as in surrounding epithelial cells. DNA-centered radicals are early intermediates formed during DNA oxidation. Once formed, DNA-centered radicals decay by mechanisms that are not completely understood, producing a number of oxidation products that are studied as markers of DNA oxidation. In this study we employed the 5,5-dimethyl-1-pyrroline N-oxide-based immuno-spin trapping technique to investigate the MPO-triggered formation of DNA-centered radicals in inflammatory and epithelial cells and to test whether resveratrol blocks HOCl-induced DNA-centered radical formation in these cells. We found that HOCl added exogenously or generated intracellularly by MPO that has been taken up by the cell or by MPO newly synthesized produces DNA-centered radicals inside cells. We also found that resveratrol passed across cell membranes and scavenged HOCl before it reacted with the genomic DNA, thus blocking DNA-centered radical formation. Taken together our results indicate that the formation of DNA-centered radicals by intracellular MPO may be a useful point of therapeutic intervention in inflammation-induced carcinogenesis.
authors.affiliation: Experimental Therapeutics Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA. sandra-gomez-mejiba@omrf.org
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Gomez-Mejiba
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhai
authors.forename: Maria S
authors.initials: MS
authors.lastname: Gimenez
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ashby
authors.forename: Jaya
authors.initials: J
authors.lastname: Chilakapati
authors.forename: Kirk
authors.initials: K
authors.lastname: Kitchin
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mason
authors.forename: Dario C
authors.initials: DC
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D005609:Free Radicals / Q000737:chemistry* / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D018922:HL-60 Cells; D054879:Halogenation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000737:chemistry / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D018736:DNA Adducts; D005609:Free Radicals; D016877:Oxidants; D013267:Stilbenes; D006997:Hypochlorous Acid; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D004247:DNA; C427203:calf thymus DNA; D006861:Hydrogen Peroxide; D009195:Peroxidase; D005978:Glutathione; D001205:Ascorbic Acid; D000077185:Resveratrol
references.citation: Chem Res Toxicol. 2002 Jan;15(1):83-92
references.pmid: 11800600
references.citation: Proc Natl Acad Sci U S A. 1988 Feb;85(4):1232-6
references.pmid: 2829220
references.citation: Nat Med. 2009 Apr;15(4):455-61
references.pmid: 19305414
references.citation: FASEB J. 2005 May;19(7):840-1
references.pmid: 15734790
references.citation: J Biol Chem. 2004 May 21;279(21):22727-37
references.pmid: 15020596
references.citation: Chem Res Toxicol. 2001 Oct;14(10):1453-64
references.pmid: 11599938
references.citation: Free Radic Biol Med. 2004 May 15;36(10):1214-23
references.pmid: 15110386
references.citation: Arch Biochem Biophys. 1996 Aug 1;332(1):110-20
references.pmid: 8806715
references.citation: Methods Enzymol. 1984;105:188-98
references.pmid: 6328178
references.citation: Br J Pharmacol. 2007 Nov;152(6):838-54
references.pmid: 17592500
references.citation: Methods Mol Biol. 2007;412:15-20
references.pmid: 18453102
references.citation: Cancer Cells. 1991 Jan;3(1):1-7
references.pmid: 2025490
references.citation: Free Radic Biol Med. 1990;8(3):231-9
references.pmid: 2160410
references.citation: Science. 1985 Mar 8;227(4691):1231-3
references.pmid: 3975611
references.citation: Clin Adv Hematol Oncol. 2009 Mar;7(3):142
references.pmid: 19402261
references.citation: Hematol Oncol Clin North Am. 1988 Jun;2(2):201-12
references.pmid: 2839456
references.citation: Toxicology. 2002 Dec 27;181-182:223-7
references.pmid: 12505315
references.citation: Biochemistry. 2000 May 9;39(18):5474-82
references.pmid: 10820020
references.citation: IUBMB Life. 2000 Oct-Nov;50(4-5):259-66
references.pmid: 11327319
references.citation: Science. 2004 Mar 5;303(5663):1532-5
references.pmid: 15001782
references.citation: Arch Biochem Biophys. 1995 Oct 20;323(1):120-6
references.pmid: 7487057
references.citation: Science. 1970 Sep 11;169(3950):1095-7
references.pmid: 4988715
references.citation: Exp Mol Med. 2009 Mar 31;41(3):171-9
references.pmid: 19293636
references.citation: Chem Biol Interact. 2009 Oct 7;181(2):193-201
references.pmid: 19523937
references.citation: Mutat Res. 2003 Oct 29;531(1-2):5-23
references.pmid: 14637244
references.citation: Free Radic Biol Med. 2009 Apr 1;46(7):853-65
references.pmid: 19159679
references.citation: Nat Protoc. 2007;2(3):512-22
references.pmid: 17406615
references.citation: Biochem Biophys Res Commun. 2003 Oct 3;309(4):1017-26
references.pmid: 13679076
references.citation: Free Radic Biol Med. 1999 Jul;27(1-2):234-40
references.pmid: 10443941
references.citation: Blood. 1983 Mar;61(3):483-92
references.pmid: 6297637
references.citation: Curr Med Chem. 2006;13(27):3271-90
references.pmid: 17168851
references.citation: Nat Chem Biol. 2008 May;4(5):278-86
references.pmid: 18421291
references.citation: Chem Res Toxicol. 2007 Jan;20(1):79-87
references.pmid: 17226929
references.citation: Eur J Clin Invest. 1991 Jun;21(3):316-22
references.pmid: 1653706
references.citation: Nat Rev Immunol. 2004 Mar;4(3):181-9
references.pmid: 15039755
references.citation: Mutagenesis. 2006 Jul;21(4):225-36
references.pmid: 16870698
references.citation: Blood. 1990 Aug 15;76(4):655-63
references.pmid: 2200535
references.citation: Science. 1981 May 1;212(4494):546-7
references.pmid: 6259738
references.citation: Toxicol Appl Pharmacol. 2007 Nov 1;224(3):274-83
references.pmid: 17306316
references.citation: Mutagenesis. 2010 Mar;25(2):149-54
references.pmid: 19892774
references.citation: Arch Biochem Biophys. 2003 Sep 1;417(1):3-11
references.pmid: 12921773
references.citation: Nat Methods. 2006 Feb;3(2):123-7
references.pmid: 16432522
references.citation: J Biol Chem. 1989 Nov 15;264(32):18996-9002
references.pmid: 2681206