Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone.
ABSTRACT Benzbromarone has been reported to increase the renal clearance of oxypurinol, an active metabolite of allopurinol. We examined the renal transport of oxypurinol to determine whether such a change in renal clearance could be explained by altered transporter-mediated reabsorption. Since the first step of reabsorption takes place at the renal epithelial apical membrane, we focused on membrane transporters. Benzbromarone is an inhibitor of reabsorption of uric acid mediated by the uric acid transporter (URAT) URAT1 (SLC22A12), which is expressed at the apical membrane of proximal tubular cells in humans. Uptake of oxypurinol by Xenopus oocytes injected with complementary RNA of URAT1 was significantly higher than that by water-injected oocytes, and the uptake was saturable, with a K(m) of about 800 microM. Moreover, benzbromarone inhibited the oxypurinol uptake by URAT1 at concentrations as low as 0.01 microM. The uptake of oxypurinol by another organic anion transporter (OAT), OAT4 (SLC22A11), which is also expressed at the apical membrane of proximal tubular epithelial cells, was negligible, whereas the uptake of [3H]estrone-3-sulfate by OAT4 was significantly inhibited by oxypurinol. Furthermore, neither the transport activity of organic cation/carnitine transporter (OCTN) 1 nor OCTN2 was affected by oxypurinol or benzbromarone. These results indicate that URAT1 is involved in renal reabsorption of oxypurinol, and the increment of renal clearance of oxypurinol upon concomitant administration of benzbromarone could be due to drug interaction at URAT1.
Article: Identification and functional characterization of uric acid transporter Urat1 (Slc22a12) in rats.[show abstract] [hide abstract]
ABSTRACT: Uric acid transporter URAT1 contributes significantly to reabsorption of uric acid in humans to maintain a constant serum uric acid (SUA) level. Since alteration of SUA level is associated with various diseases, it is important to clarify the mechanism of change in SUA. However, although expression of mRNA of an ortholog of URAT1 (rUrat1) in rats has been reported, functional analysis and localization have not been done. Therefore, rat rUrat1 was functionally analyzed using gene expression systems and isolated brush-border membrane vesicles (BBMVs) prepared from rat kidney, and its localization in kidney was examined immunohistochemically. Uric acid transport by rUrat1 was chloride (Cl-) susceptible with a Km of 1773μM. It was inhibited by benzbromarone and trans-stimulated by lactate and pyrazinecarboxylic acid (PZA). Cl- gradient-susceptible uric acid transport by BBMVs showed similar characteristics to those of uric acid transport by rUrat1. Moreover, rUrat1 was localized at the apical membrane in proximal tubular epithelial cells in rat kidney. Accordingly, rUrat1 is considered to be involved in uric acid reabsorption in rats in the same manner as URAT1 in humans. Therefore, rUrat1 may be a useful model to study issues related to the role of human URAT1.Biochimica et Biophysica Acta 11/2010; 1808(6):1441-7. · 4.66 Impact Factor
Article: Functional cooperation of URAT1 (SLC22A12) and URATv1 (SLC2A9) in renal reabsorption of urate.[show abstract] [hide abstract]
ABSTRACT: Background Serum urate (SUA) level is affected by alteration in urinary reabsorption caused by clinically important drugs; however, there are no experimental models suitable to assess their effect on renal reabsorption. We, therefore, aimed to establish an experimental system co-expressing the urate transporters URAT1 (SLC22A12) and URATv1 (SLC2A9) (designated UUv cells) at the apical and basolateral membranes, respectively.Methods Apical uptake and vectorial transport of [(14)C]urate in the apical-to-basolateral direction in UUv cells were measured in the presence or absence of uricosuric benzbromarone or anti-uricosuric trans-stimulators.ResultsThe urate permeability in the apical-to-basolateral direction remarkably increased by 7.0-fold in UUv cells, compared with non-transfected mock cells. The apical-to-basolateral transport was cis-inhibited by benzbromarone, but trans-stimulated by pyrazinecarboxylic acid and monocarboxylates such as nicotinate and lactate. Furthermore, salicylate showed both trans-stimulation and cis-inhibition in the urate transport at low and high concentrations, respectively. Finally, coexpression of URAT1 and URATv1 in human kidney epithelial cells was exhibited immunohistochemically.Conclusions It is demonstrated that functional cooperation of URAT1 and URATv1 is essential for renal reabsorption of urate, and in the established system influence of drugs on SUA is reflected in the alteration of urate permeability across the renal tubular epithelial cells.Nephrology Dialysis Transplantation 01/2013; · 3.40 Impact Factor