Dityrosine, a specific marker of oxidation, is synthesized by the myeloperoxidase-hydrogen peroxide system of human neutrophils and macrophages.

Myeloperoxidase, secreted by activated phagocytes, produces the powerful cytotoxin hypochlorous acid from H2O2 and Cl-. We show that the enzyme can also employ H2O2 to oxidize L-tyrosine to tyrosyl radical, yielding the stable cross-linked product dityrosine. Dityrosine synthesis by the myeloperoxidase-H2O2 system did not require halide and was partially inhibited by Cl-. At physiological concentrations of Cl-, L-tyrosine, and other plasma amino acids, purified myeloperoxidase utilized 26% of the H2O2 in the reaction mixture to form dityrosine. Aminotriazole, cyanide, and azide inhibited the reaction. Phorbol ester-stimulated human neutrophils and monocyte-derived macrophages similarly generated dityrosine from L-tyrosine by a pathway inhibited by catalase, aminotriazole, and azide. The requirement for H2O2 and the inhibition by heme poisons suggest that activated phagocytes synthesize dityrosine by a peroxidative mechanism. These results indicate that L-tyrosine can compete effectively with Cl- as a substrate for myeloperoxidase and raise the possibility that formation of tyrosyl radical may play a role in the phagocyte inflammatory response. Because dityrosine is protease-resistant, stable to acid hydrolysis, and intensely fluorescent, its identification in tissues may pinpoint targets where phagocytes inflict oxidative damage in vivo.