Myeloperoxidase-induced genomic DNA-centered radicals.
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.
Gomez-Mejiba
Sandra E
SE
Experimental Therapeutics Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA. sandra-gomez-mejiba@omrf.org
Zhai
Zili
Z
Gimenez
Maria S
MS
Ashby
Michael T
MT
Chilakapati
Jaya
J
Kitchin
Kirk
K
Mason
Ronald P
RP
Ramirez
Dario C
DC
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
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
Chem Res Toxicol. 2002 Jan;15(1):83-92
11800600
Proc Natl Acad Sci U S A. 1988 Feb;85(4):1232-6
2829220
Nat Med. 2009 Apr;15(4):455-61
19305414
FASEB J. 2005 May;19(7):840-1
15734790
J Biol Chem. 2004 May 21;279(21):22727-37
15020596
Chem Res Toxicol. 2001 Oct;14(10):1453-64
11599938
Free Radic Biol Med. 2004 May 15;36(10):1214-23
15110386
Arch Biochem Biophys. 1996 Aug 1;332(1):110-20
8806715
Methods Enzymol. 1984;105:188-98
6328178
Br J Pharmacol. 2007 Nov;152(6):838-54
17592500
Methods Mol Biol. 2007;412:15-20
18453102
Cancer Cells. 1991 Jan;3(1):1-7
2025490
Free Radic Biol Med. 1990;8(3):231-9
2160410
Science. 1985 Mar 8;227(4691):1231-3
3975611
Clin Adv Hematol Oncol. 2009 Mar;7(3):142
19402261
Hematol Oncol Clin North Am. 1988 Jun;2(2):201-12
2839456
Toxicology. 2002 Dec 27;181-182:223-7
12505315
Biochemistry. 2000 May 9;39(18):5474-82
10820020
IUBMB Life. 2000 Oct-Nov;50(4-5):259-66
11327319
Science. 2004 Mar 5;303(5663):1532-5
15001782
Arch Biochem Biophys. 1995 Oct 20;323(1):120-6
7487057
Science. 1970 Sep 11;169(3950):1095-7
4988715
Exp Mol Med. 2009 Mar 31;41(3):171-9
19293636
Chem Biol Interact. 2009 Oct 7;181(2):193-201
19523937
Mutat Res. 2003 Oct 29;531(1-2):5-23
14637244
Free Radic Biol Med. 2009 Apr 1;46(7):853-65
19159679
Nat Protoc. 2007;2(3):512-22
17406615
Biochem Biophys Res Commun. 2003 Oct 3;309(4):1017-26
13679076
Free Radic Biol Med. 1999 Jul;27(1-2):234-40
10443941
Blood. 1983 Mar;61(3):483-92
6297637
Curr Med Chem. 2006;13(27):3271-90
17168851
Nat Chem Biol. 2008 May;4(5):278-86
18421291
Chem Res Toxicol. 2007 Jan;20(1):79-87
17226929
Eur J Clin Invest. 1991 Jun;21(3):316-22
1653706
Nat Rev Immunol. 2004 Mar;4(3):181-9
15039755
Mutagenesis. 2006 Jul;21(4):225-36
16870698
Blood. 1990 Aug 15;76(4):655-63
2200535
Science. 1981 May 1;212(4494):546-7
6259738
Toxicol Appl Pharmacol. 2007 Nov 1;224(3):274-83
17306316
Mutagenesis. 2010 Mar;25(2):149-54
19892774
Arch Biochem Biophys. 2003 Sep 1;417(1):3-11
12921773
Nat Methods. 2006 Feb;3(2):123-7
16432522
J Biol Chem. 1989 Nov 15;264(32):18996-9002
2681206