Generation of allantoin from the oxidation of urate by cytochrome c and its possible role in Reye's syndrome

Abstract

Allantoin in the presence of calcium ions has been implicated as a potential toxic agent in Reye's syndrome. An investigation of possible alternative sources of allantoin in humans, which lack the enzyme uricase, has been initiated. Urate is a strong reducing agent which can reduce cytochrome c nonenzymatically, with the concomitant production of CO 2 and H +. The stoichiometries measured for the various reactants and products were 1 urate:2 cytochrome c:1 H +:1 CO 2. The initial reaction rate depended on the concentrations of both urate and cytochrome c, with reaction kinetics that were first order with respect to urate and second order with respect to cytochrome c. The participation of molecular oxygen in this reaction could not be detected. The pH and ionic strength optima for this reaction were determined to be 9.5–10.5 and 10 −5 m, respectively. Based on the results reported here, the following balanced equation can be written: urate −2 + 2 cytochrome c +3 + 2 H 2O → allantoin + 2 cytochrome c +2 + H + + HCO 3 −. We propose that allantoin can be generated from the oxidation of urate by cytochrome c +3, and that this is a potential source of allantoin in human tissues.