Uricosuric targets of tranilast

Abstract

Uric acid, generated from the metabolism of purines, has both proven and emerging roles in human disease. Serum uric acid in humans is determined by production and by the net balance of reabsorption and secretion in kidney and intestine. In the human kidney, epithelial reabsorption dominates over secretion, such that in normal subjects there is at least 90% net reabsorption of filtered urate resulting in a fractional excretion of <10%. Tranilast, an anti‐inflammatory drug with pleiotropic effects, has a marked hypouricemic, uricosuric effect in humans. We report here that tranilast is a potent inhibitor of [14C]‐urate transport mediated by the major reabsorptive urate transporters (URAT1, GLUT9, OAT4, and OAT10) in Xenopus oocytes; this provides an unequivocal molecular mechanism for the drug's uricosuric effect. Tranilast was found to inhibit urate transport mediated by URAT1 and GLUT9 in a fully reversible and noncompetitive (mixed) manner. In addition, tranilast inhibits the secretory urate transporters NPT1, OAT1, and OAT3 without affecting the secretory efflux pump ABCG2. Notably, while benzbromarone and probenecid inhibited urate as well as nicotinate transport, tranilast inhibited the urate transport function of URAT1, GLUT9, OAT4, OAT10, and NPT1, without significantly affecting nicotinate transport mediated by SMCT1 (IC 50 ~1.1 mmol/L), SMCT2 (IC 50 ~1.0 mmol/L), and URAT1 (IC 50 ~178 μmol/L). In summary, tranilast causes uricosuria by inhibiting all the major reabsorptive urate transporters, selectively affecting urate over nicotinate transport. These data have implications for the treatment of hyperuricemia and gout, the pharmacology of tranilast, and the structure‐function analysis of urate transport.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

“…OAT7 is a hepatic transport protein that exchanges, for the short chain fatty acid butyrate, sulphyl conjugates, xenobiotics and steroid hormones and is not inhibited by established inhibitors and substrates of other organic anion transporters such as probenecid, paraaminohippurate, nonsteroidal anti-inflammatory drugs and diuretics [36]. We found that urate transport mediated by OAT7 is inhibited by the uricosuric drugs benzbromarone and tranilast, which inhibit multiple other urate transporters [50]. Three uncommon missense variants that influence the ability of OAT7 to transport pravastatin by either causing the protein to be retained intracellularly or reducing protein levels at the plasma membrane have been reported [51], all at a frequency < 1% in East Asian.…”

“…Studies using Xenopus laevis oocytes were performed in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the U.S. National Institutes of Health, and were approved by the Institution’s Animal Care and Use Committee. Mature female Xenopus laevis frogs (NASCO, Fort Atkinson, MI) were subjected to partial ovariectomy under tricane (SIGMA St Louis, MO) anesthesia (0.17% for 15–20 min) as described previously [50]. A small incision was made in the abdomen and a lobe of ovary was removed.…”

Population‐Specific Resequencing Associates the ATP‐Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men

“…ABCC4 exported uric acid at an approximately 2-fold slower rate than ABCG2 (data not shown and (33)). Unlike ABCG2 (33), ABCC4 was sensitive to tranilast and benzbromarone, in addition to 1.0 mM probenecid (Figure 2A).…”

“…ABCC4 exported uric acid at an approximately 2-fold slower rate than ABCG2 (data not shown and (33)). Unlike ABCG2 (33), ABCC4 was sensitive to tranilast and benzbromarone, in addition to 1.0 mM probenecid (Figure 2A). The presence of a leucine residue at position 1036 led to an approximately 35% reduction in uric acid efflux, with no effect on protein expression (Figure 2B).…”

“…In each case the fidelity of mutagenesis was assessed by sequencing the entire open reading frame. Transport function of wild-type and mutant ABCC4 was then assessed using 14 C-urate efflux in individual Xenopus laevis oocytes, as previously described for ABCG2 (12, 33). Collagenase-digested oocytes were thus micro-injected with in vitro -transcribed cRNA (25 ng/oocyte) for each construct, followed by transport assays after two days in culture.…”