Uricolysis in normal and gouty individuals.

One of the many theories of gout has been that the hyperuricaemia in gout is due to a defect in uricolysis. Uricase has never been demonstrated in human tissue; thus this argument is on tenuous ground. In the determination of the uric acid pool and turnover rate, Benedict and others (1949) consistently observed a discrepancy between turnover rate and excretion which they designated the uric acid excess. The excess could only be partly explained by sweating and loss through internal secretions such as the bile. In their experiments, the amount of N15 uric acid injected for the pool determination was low, and the extent of labelling of the nitrogenous products in the urine, other than uric acid, was not much greater than the natural abundance. Utilizing large doses of N15 uric acid in an effort to demonstrate significant enrichment of the urea and ammonia in urine, Wyngaarden and Stetten (1953) demonstrated significant uricolysis in normal man. It was determined that 18 per cent. of an intravenously administered dose of uric acid was degraded to other nitrogenous products that appeared in the urine, 6 per cent. was excreted in the faeces, and 78 per cent. was excreted as unchanged uric acid in a 2-week period. Repetition of the experiment in the same subject, with intestinal bacteriostasis accomplished with oral phthalylsulphathiazole, yielded essentially the same results. This was interpreted as an indication that degradation of urate by intestinal flora was not a major source of uricolysis. It was important to demonstrate that uricolysis did not depend on the uric acid content of bile and the alkaline reaction of pancreatic juice. We have incubated juice with and without bile under sterile conditions (Seitz filtered) with dilute uric acid solutions. The rate of uric acid disappearance was measured by change of absorption at 292 ptu. in a Beckman du Quartz spectrophotometer, and by total chromogen determinations by the method of Kern and Stransky, modified by Archibald (Forsham and others, 1948); 5 per cent. of the uric acid had been destroyed at the end of a 2-hour period, and 15 per cent. at the end of a 5-hour period. Since the pH of the duodenal secretions varied from 7 0 to 8 * 8, and would normally be much lower in man because of the acidity of the gastric contents, significant uricolysis cannot be accounted for by this route. In the above experiment, marked uricolysis occurred rapidly if there was bacterial contamination of the preparations. Geren and others (1950) demonstrated the difference in fate of oral and intravenous urate, more than 91 per cent. being degraded after oral administration. The observations of Margules and Griffiths (1950) and Griffiths (1952) demonstrated the oxidation of uric acid at a physiological pH in the presence of a cytochrome-cytochrome oxidase system; Griffiths concluded that it is possible for urate to be oxidized in small quantities in organisms lacking uricase. Another uricolytic system at a physiological pH was reported by Tuttle and Cohen (1953); using leucoperoxidase coupled with a glucose-glucose oxidase system as a source of peroxide, and in the presence of C14 uric acid, these authors were able to demonstrate the degradation products of uric acid in this system as 33 per cent. allantoin and 20 per cent. urea. Urate incubated with uricase gave a 90 per cent. yield of allantoin. The nitrogen excretion as urea and ammonia in Wyngaarden's experiment could possibly be explained on the basis of peroxidase degradation. The uric acid degradation products involved in the cytochrome-cytochrome oxidase system have not yet been investigated. It is apparent, then, that although uricase is lacking, there exist in humans at least two enzymes capable of oxidase. White blood cells contain approximately 2 per cent. verdo-peroxidase, and red blood cells have both peroxidase and cytochrome-oxidase activity. A fall in serum urate levels in blood from which the,