Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients

Oxidative stress has been implicated in the cardiovascular complications th at affect chronic renal failure patients on hemodialysis, though the physio logically relevant pathways mediating oxidative damage are poorly understoo d. It is known, however, that hemodialysis activates neutrophils, a well-ch aracterized source of hydrogen peroxide and myeloperoxidase. The phagocyte- derived myeloperoxidase-hydrogen peroxide-chloride system generates hypochl orous acid, which reacts with tyrosine residues of proteins to form 3-chlor otyrosine. To explore the role of activated phagocytes in oxidative stress in chronic renal failure, we used 3-chlorotyrosine as a specific marker of myeloperoxidase activity. Utilizing isotope dilution gas chromatography-mas s spectrometry, we compared 3-chlorotyrosine levels in plasma proteins of f ive patients on chronic hemodialysis therapy with those of age- and sex-mat ched healthy controls. The oxidized amino acid was present in the plasma pr oteins of 4 of the hemodialysis patients (3.5 +/- 0.8 mu mol per mol tyrosi ne) but was undetectable in the healthy subjects. Therefore, one pathway fo r oxidative stress in hemodialysis patients appears to involve hypochlorous acid generated by the myeloperoxidase. system of activated phagocytes. We also examined intradialytic 3-chlorotyrosine levels using membranes that ac tivate white blood cells and the alternative pathway of complement. Hemodia lysis increased plasma myeloperoxidase and the expression of CD11b/CD18 by circulating phagocytes, but failed to demonstrably increase 3-chlorotyrosin e levels. 3-chlorotyrosine was detectable in 12 of 19 samples in total, wit h significant intrasubject variability. Our observations suggest that oxida nts generated by myeloperoxidase contribute to the increased oxidative stre ss observed in renal-failure patients but do not damage plasma proteins dur ing the hemodialysis procedure itself. (C) 2001 Elsevier Science Inc.