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 ≤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.

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

“…However, we are not the first to observe dissociation between urate and oxidative stress indices, protein carbonyl levels in particular. Clinical studies have revealed higher or unchanged protein carbonyls in patients with high urate, including refractory gout patients (30)(31)(32). Furthermore, urate has the capacity to act as a prooxidant under some circumstances (33)(34)(35).…”

Evolutionary history and metabolic insights of ancient mammalian uricases

“…Uric acid is recognized as an antioxidant and it has been hypothesized to be an important antioxidant in the plasma (9), although its role in oxidative stress has been disputed (10). More recently, uric acid has been implicated in metabolic syndrome and fat accumulation (2,(11)(12)(13).…”

What Are the Key Arguments Against Uric Acid as a True Risk Factor for Hypertension?

“…For example, studies in humans show that the lowering of uric acid with uricase does not result in increased oxida tive stress, but if anything tends to reduce oxidative stress. 28 Furthermore, the reaction of uric acid with peroxynitrite is not benign, but generates alkylating species and radicals (amino carbonyl and triuretcarbonyl). 29,30 Indeed, the administration of inosine to raise uric acid levels was ineffective in subjects with multiple sclerosis in one study, 31 with minimal benefit in another.…”