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 m utagenesis in adjacent epithelial cells. Eosinophil peroxidase, a heme enzy me released by eosinophils, generates hypobromous acid that damages tissue in inflammatory conditions. We show that human eosinophils use eosinophil p eroxidase to produce 5-bromodeoxycytidine. Flow cytometric, immunohistochem ical, and mass spectrometric analyses all demonstrated that 5-bromodeoxycyt idine generated by eosinophil peroxidase was taken up by cultured cells and incorporated into genomic DNA as 5-bromodeoxyuridine. Although previous st udies have focused on oxidation of chromosomal DNA, our observations sugges t another mechanism for oxidative damage of DNA, In this scenario, peroxida se-catalyzed halogenation of nucleotide precursors yields products that sub sequently can be incorporated into DNA, Because the thymine analog 5-BrUra mispairs with guanine in DNA, generation of brominated pyrimidines by eosin ophils might constitute a mechanism for cytotoxicity and mutagenesis at sit es of inflammation.