Production of brominating intermediates by myeloperoxidase - A transhalogenation pathway for generating mutagenic nucleobases during inflammation

The existence of interhalogen compounds was proposed more than a century ag o, but no biological roles have been attributed to these highly oxidizing i ntermediates. In this study, we determined whether the peroxidases of white blood cells can generate the interhalogen gas bromine chloride (BrCl), Mye loperoxidase, the heme enzyme secreted by activated neutrophils and monocyt es, uses H2O2 and Cl- to produce HOCl, a chlorinating intermediate. In cont rast, eosinophil peroxidase preferentially converts Br- to HOBr, Remarkably , both myeloperoxidase and eosinophil peroxidase were able to brominate deo xycytidine, a nucleoside, and uracil, a nucleo,ase, at plasma concentration s of Br- (100 muM) and Cl- (100 mM). The two enzymes used different reactio n pathways, however. When HOCl brominated deoxycytidine, the reaction requi red Br- and was inhibited by taurine. In contrast, bromination by HOBr was independent of Br- and unaffected by taurine, Moreover, taurine inhibited 5 -bromodeoxycytidine production by the myeloperoxidase-H2O2-Cl-- Br- system but not by the eosinophil peroxidase-H2O2-Cl--Br- system, indicating that b romination by myeloperoxidase involves the initial production of HOCl. Both HOCl-Br- and the myeloperoxidase-H2O2-Cl--Br- system generated a gas that converted cyclohexene into 1-bromo-2-chlorocyclohexane, implicating BrCl in the reaction. Moreover, human neutrophils used myeloperoxidase, H2O2, and Br- to brominate deoxycytidine by a taurine-sensitive pathway, suggesting t hat transhalogenation reactions may be physiologically relevant. 5-Bromoura cil incorporated into nuclear DNA is a well known mutagen. Our observations therefore raise the possibility that transhalogenation reactions initiated by phagocytes provide one pathway for mutagenesis and cytotoxicity at site s of inflammation.