Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients.
Oxidative stress has been implicated in the cardiovascular complications that affect chronic renal failure patients on hemodialysis, though the physiologically relevant pathways mediating oxidative damage are poorly understood. It is known, however, that hemodialysis activates neutrophils, a well-characterized source of hydrogen peroxide and myeloperoxidase. The phagocyte-derived myeloperoxidase-hydrogen peroxide-chloride system generates hypochlorous acid, which reacts with tyrosine residues of proteins to form 3-chlorotyrosine. 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-mass spectrometry, we compared 3-chlorotyrosine levels in plasma proteins of five patients on chronic hemodialysis therapy with those of age- and sex-matched healthy controls. The oxidized amino acid was present in the plasma proteins of 4 of the hemodialysis patients (3.5 +/- 0.8 micromol per mol tyrosine) but was undetectable in the healthy subjects. Therefore, one pathway for 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 activate white blood cells and the alternative pathway of complement. Hemodialysis increased plasma myeloperoxidase and the expression of CD11b/CD18 by circulating phagocytes, but failed to demonstrably increase 3-chlorotyrosine levels. 3-chlorotyrosine was detectable in 12 of 19 samples in total, with significant intrasubject variability. Our observations suggest that oxidants generated by myeloperoxidase contribute to the increased oxidative stress observed in renal-failure patients but do not damage plasma proteins during the hemodialysis procedure itself.
Himmelfarb
J
J
Division of Nephrology, Maine Medical Center, Portland, ME 04102, USA. himmej@mmc.org
McMenamin
M E
ME
Loseto
G
G
Heinecke
J W
JW
D000328:Adult; D000368:Aged; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism*; D010586:Phagocytes / Q000378:metabolism*; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000097:blood* / Q000201:enzymology / Q000276:immunology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood*
D001798:Blood Proteins; D014443:Tyrosine; D009195:Peroxidase; C087259:3-chlorotyrosine