Morin (3,5,7,2′,4′-pentahydroxyflavone) exhibits potent inhibitory actions on urate transport by the human urate anion transporter (hURAT1) expressed in human embryonic kidney cells
Morin (3,5,7,2′,4′-pentahydroxyflavone) exhibits potent inhibitory actions on urate transport by the human urate anion transporter (hURAT1) expressed in human embryonic kidney cells
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DOI：
10.1124/dmd.106.012187
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发表时间：
2007-06-01
影响因子：
3.9
通讯作者：
Cheng, Christopher H. K.
中科院分区：
文献类型：
--
作者：
Yu, Zhifeng;Fong, Wing Ping;Cheng, Christopher H. K.
在别嘌呤醇过敏患者中，促尿酸药物常用于治疗高尿酸血症。现有的促尿酸排泄剂并非没有问题，并且非常需要更好和更安全的替代品的可用性。我们先前的研究（J Pharmacol Exp Ther（2006）316：169-175）已经证明，桑色素（3，5，7，2 ′，4 ′-五羟基黄酮），其存在于桑树的枝条中。在中国传统医学文献中记载用于治疗类似痛风的病症，是大鼠肾刷状缘膜囊泡中尿酸盐摄取的有效抑制剂。在体内高尿酸血症大鼠模型中，它也能有效降低尿酸水平。桑色素是否是一种同样有效的促尿酸排泄剂在人类需要验证。人尿酸盐阴离子转运蛋白1（human urate anion transporter，hURAT 1）是近年来发现的一种介导尿酸盐重吸收的有机阴离子转运蛋白。在本研究中，用hURAT 1转染人胚肾细胞，并通过逆转录-聚合酶链反应和共聚焦显微镜观察外源引入的转运蛋白的亚细胞分布来验证表达。利用该系统研究了桑色素对人肾尿酸盐重吸收的抑制作用。桑色素抑制的IC 50值测定为2.0 μ M，而丙磺舒为50 μ M，磺胺草酮为100 μ M，苯溴马隆为0.3 μ M。桑色素摄取抑制的动力学分析表明，该化合物是人尿酸盐转运蛋白上尿酸盐摄取的竞争性抑制剂，Ki值为5.74 μ M。
In allopurinol-allergic patients, uricosuric agents are often used in the treatment of hyperuricemia. The existing uricosuric agents are not without problems and the availability of better and safer alternatives is highly desirable. Our previous study (J Pharmacol Exp Ther (2006) 316:169-175) has demonstrated that morin (3,5,7,2',4'-pentahydroxyflavone), which occurs in the twigs of Morus alba L. documented in traditional Chinese medicinal literature for treatment of conditions akin to gout, is a potent inhibitor of urate uptake in rat renal brush-border membrane vesicles. It is also effective in lowering uric acid level in a hyperuricemic rat model in vivo. Whether morin is an equally effective uricosuric agent in human requires verification. The human urate anion transporter (hURAT1) has recently been cloned and identified to be the organic anion transporter that mediates renal urate reabsorption in the human kidney. In the present investigation, human embryonic kidney cells were transfected with hURAT1 and the expression was validated by reverse transcription-polymerase chain reaction and subcellular distribution of the exogenously introduced transporter by confocal microscopy. The inhibitory actions of morin on human renal urate reabsorption were demonstrated using this system. The IC50 value of the inhibition by morin was determined to be 2.0 mu M, compared with 50 mu M for probenecid, 100 mu M for sulfinpyrazone, and 0.3 mu M for benzbromarone. Kinetic analysis of the uptake inhibition by morin indicates that this compound is a competitive inhibitor of urate uptake on the human urate transporter with a K-i value of 5.74 mu M.