Bromination of deoxycytidine by eosinophil peroxidase: a mechanism for mutagenesis by oxidative damage of nucleotide precursors.
Oxidants generated by eosinophils during chronic inflammation may lead to mutagenesis in adjacent epithelial cells. Eosinophil peroxidase, a heme enzyme released by eosinophils, generates hypobromous acid that damages tissue in inflammatory conditions. We show that human eosinophils use eosinophil peroxidase to produce 5-bromodeoxycytidine. Flow cytometric, immunohistochemical, and mass spectrometric analyses all demonstrated that 5-bromodeoxycytidine generated by eosinophil peroxidase was taken up by cultured cells and incorporated into genomic DNA as 5-bromodeoxyuridine. Although previous studies have focused on oxidation of chromosomal DNA, our observations suggest another mechanism for oxidative damage of DNA. In this scenario, peroxidase-catalyzed halogenation of nucleotide precursors yields products that subsequently can be incorporated into DNA. Because the thymine analog 5-BrUra mispairs with guanine in DNA, generation of brominated pyrimidines by eosinophils might constitute a mechanism for cytotoxicity and mutagenesis at sites of inflammation.
Henderson
J P
JP
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Byun
J
J
Williams
M V
MV
McCormick
M L
ML
Parks
W C
WC
Ridnour
L A
LA
Heinecke
J W
JW
D000818:Animals; D001966:Bromine; D001973:Bromodeoxyuridine / Q000378:metabolism; D016466:CHO Cells; D002384:Catalysis; D006224:Cricetinae; D003596:Cytosine / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003841:Deoxycytidine / Q000378:metabolism*; D047209:Eosinophil Peroxidase; D004804:Eosinophils / Q000201:enzymology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016296:Mutagenesis; D009711:Nucleotides; D010544:Peroxidases / Q000378:metabolism*; D013552:Swine
D009711:Nucleotides; D003841:Deoxycytidine; D003596:Cytosine; D004247:DNA; D006861:Hydrogen Peroxide; D047209:Eosinophil Peroxidase; D010544:Peroxidases; D001973:Bromodeoxyuridine; D001966:Bromine