Uricosuric targets of tranilast.
Uricosuric targets of tranilast.
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DOI：
10.1002/prp2.291
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发表时间：
2017-04
影响因子：
2.6
通讯作者：
Mount DB
中科院分区：
文献类型：
--
作者：
Mandal AK;Mercado A;Foster A;Zandi-Nejad K;Mount DB
尿酸是由嘌呤代谢产生的，在人类疾病中既有已被证实的作用，也有新的作用。人体的血尿酸是由尿酸的产生以及肾脏和肠道的重吸收和分泌的净平衡决定的。在人类肾脏中，上皮重吸收超过分泌，因此在正常受试者中，至少有90%的过滤尿酸盐净重吸收，导致部分排泄<；10%。曲尼司特是一种具有多效性的抗炎药物，在人体内具有显著的低尿酸血症和尿酸作用。我们在这里报道，曲尼司特是一种有效的抑制[14C]-尿酸转运的药物，它是由非洲爪哇卵母细胞中主要的重吸收尿酸转运体(URAT1，GLUT9，OAT4和OAT10)介导的；这为该药物的尿尿酸效应提供了明确的分子机制。曲尼司特以完全可逆和非竞争性(混合)的方式抑制URAT1和GLUT9介导的尿酸转运。此外，曲尼司特抑制分泌尿酸转运体NPT1、OAT1和OAT3，而不影响分泌外排泵ABCG2。曲尼司特抑制URAT1、GLUT9、OAT4、OAT10和NPT1的尿酸转运功能，但对SMCT1(IC50~1.1mmoL/L)、SMCT2(IC50~1.0mmoL/L)和URAT1(IC50~178mmoL/L)介导的烟酸转运无明显影响。综上所述，曲尼司特通过抑制所有主要的重吸收尿酸盐转运体，选择性地影响尿酸盐对烟酸盐的转运体，从而导致尿酸尿。这些数据对高尿酸血症和痛风的治疗、曲尼司特的药理学和尿酸盐转运的结构-功能分析具有重要意义。
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.