Overproduction of uric acid as the cause of hyperuricemia in primary gout.

Glycine contributes carbon atoms 4 and 5 and nitrogen atom 7 of the purine ring (1-3). Benedict, Yfi, Bien, Gutman and Stetten (4) have described experiments in which the abundance of N15 in uric acid was measured for several days following an oral test dose of glycine-N'5. In two gouty subjects, three times as much of the administered N15 was recovered in urinary uric acid as in normal subjects. In two others, however, normal quantities of N15 appeared in uric acid. In these studies, there was a rank order correlation between the daily excretion of uric acid in the urine and the per cent of ingested isotope appearing in urinary uric acid. In subjects who exhibited abnormally high basal uric acid excretions, an abnormally rapid and excessive incorporation of dietary glycine into uric acid occurred. In others whose basal excretion was approximately normal, utilization of glycine for uric acid synthesis was normal. Muller and Bauer (5) and Bishop, Rand, and Talbott (6) have each reported an additional gouty patient excreting normal quantities of uric acid who incorporated normal quantities of glycine-N'5 into urinary uric acid. The latter authors also described one gouty patient who incorporated excessive quantities of glycine-N'5 into urinary uric acid on two of three occasions despite a normal urinary urate excretion. These studies, therefore, demonstrated that overproduction of uric acid was present in some gouty subjects, but failed to give a clear indication of the cause of hyperuricemia in another, perhaps predominant group of the gouty population. Recently, we have administered glycine-1-C'4 to control and gouty patients in order to label urinary purines, as part of a study of intermediates in urate synthesis (7). The first two gouty patients both exhibited excessive incorporation of C14 into urinary urate, one despite a normal urate excretion (7, 8). It was therefore decided to re-investigate the problem of the rate of generation of uric acid in gout, employing tracer doses of glycine-1-C"4 rather than large doses of glycine-N'5 as were required in previous studies. In the present study, glycine-1-C'4 was administered orally in 2.5 to 25 uc. doses to control and gouty subjects, and the concentration and cumulative incorporation of isotope into urinary uric acid were determined. This paper presents data indicating that overincorporation of glycine-1-C'4 into uric acid is a consistent finding in primary gout, and that the failure of the glycine-N'5 technique to disclose overincorporation in some gouty subjects may have been the result of the large dose of glycine employed. These results have been interpreted as showing that the hyperuricemia of primary gout is due to overproduction of uric acid in the majority if not all gouty subjects.