title: Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo.
abstract: A high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support rests largely on in vitro data and epidemiologic associations. Pegloticase therapy generates H(2)O(2) while depleting urate, offering an in vivo test of the antioxidant hypothesis. We show that erythrocytes can efficiently eliminate H(2)O(2) derived from urate oxidation to prevent cell injury in vitro; during therapy, disulfide-linked peroxiredoxin 2 dimer did not accumulate in red blood cells, indicating that their peroxidase capacity was not exceeded. To assess oxidative stress, we monitored F2-Isoprostanes (F2-IsoPs) and protein carbonyls (PC), products of arachidonic acid and protein oxidation, in plasma of 26 refractory gout patients receiving up to five infusions of pegloticase at 3-wk intervals. At baseline, PUA was markedly elevated in all patients, and plasma F2-IsoP concentration was elevated in most. Pegloticase infusion rapidly lowered mean PUA to < or = 1 mg/dL in all patients, and PUA remained low in 16 of 21 patients who completed treatment. F2-IsoP levels did not correlate with PUA and did not increase during 15 wk of sustained urate depletion. There also was no significant change in the levels of plasma PC. Because refractory gout is associated with high oxidative stress in spite of high PUA, and profoundly depleting uric acid did not increase lipid or protein oxidation, we conclude that urate is not a major factor controlling oxidative stress in vivo.
authors.affiliation: Division of Rheumatology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. msh@biochem.duke.edu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Ganson
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Kelly
authors.forename: Ines
authors.initials: I
authors.lastname: Santisteban
authors.forename: Edna
authors.initials: E
authors.lastname: Scarlett
authors.forename: Denise
authors.initials: D
authors.lastname: Jaggers
authors.forename: John S
authors.initials: JS
authors.lastname: Sundy
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D028441:F2-Isoprostanes / Q000378:metabolism; D006073:Gout / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011092:Polyethylene Glycols; D011506:Proteins / Q000378:metabolism; D014503:Urate Oxidase / Q000008:administration & dosage* / Q000627:therapeutic use; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D028441:F2-Isoprostanes; D011506:Proteins; D014527:Uric Acid; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D014503:Urate Oxidase