Abstract
Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats.
Highlights
Uric acid is a final product of purine nucleoside metabolism in humans, and it is thought that its level is well controlled, mainly by the balance between production in liver from purine nucleosides and excretion into urine
We investigated the contribution and molecular mechanism of extra-renal elimination of uric acid
Since elevated serum uric acid (SUA) has been reported to be associated with several diseases [3,4], an understanding of the mechanism of uric acid disposition is important in order to control SUA level
Summary
Uric acid is a final product of purine nucleoside metabolism in humans, and it is thought that its level is well controlled, mainly by the balance between production in liver from purine nucleosides and excretion into urine. It has been suggested that serum uric acid (SUA) should be kept below 7 mg/dL to prevent hyperuricemia, which is a clinically important risk factor for cardiovascular diseases, chronic kidney disease and gout [3,4]. Salicylic acid causes an increase in SUA level at low dose, but a decrease at high dose [9].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
