Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition
Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition
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去甲甲状腺醇作为新的候选降尿酸药物的双重作用：促尿酸排泄作用和黄嘌呤氧化酶抑制
DOI：
10.1016/j.ejphar.2019.04.034
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发表时间：
2019-06
影响因子：
5
通讯作者：
Li Ling
中科院分区：
文献类型：
--
作者：
Lin Hua;Tu Caixia;Niu Yanfen;Li Fashuang;Yuan Lixian;Li Na;Xu Aiping;Gao Lihui;Li Ling
高尿酸血症是由尿酸分泌过多和排泄不足引起的，与慢性肾功能障碍、心血管疾病、糖尿病和代谢综合征有关。然而，现有的临床药物不能同时针对尿酸的产生和排泄。去甲三醇是一种天然的xanthone，被认为具有双重作用。我们以前报道过去甲三醇具有很强的抗高尿酸血症活性，这与抑制尿酸的产生有关。在这里，我们研究了高尿酸血症动物的尿酸作用，并探索了与肾脏尿酸转运体和黄嘌呤氧化酶(XO)相关的可能的分子机制。结果表明，去甲三醇(0.5~4.0 mg/kg)呈剂量和时间依赖性地降低尿酸诱导的高尿酸血症小鼠的血尿酸水平，显著增加氧酸盐诱导的高尿酸血症大鼠的尿酸排泄分数，对肾脏尿酸排泄有促进作用。进一步的证据表明，去甲三醇能显著增加高尿酸血症小鼠肾脏分泌型有机阴离子转运体1(OAT1)的mRNA和蛋白表达，增强其体外转运功能。此外，去甲三醇还上调了分泌转运蛋白OAT3、ATP结合盒转运蛋白G2和多药耐药蛋白4的mRNA表达，但不上调其蛋白表达。未观察到重吸收转运蛋白表达的变化。这是去甲三醇通过靶向OAT1而具有尿酸尿作用的第一个报道。此外，去甲三醇以非竞争性方式显著抑制XO活性。综上所述，这些发现表明去甲三醇有可能被开发为一种具有激活OAT1和抑制XO活性的双重作用的新型抗高尿酸血症药物。
Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5–4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.
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影响因子：
--
作者：
R. Pelis;S. Wright
通讯作者：
R. Pelis;S. Wright
影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H
影响因子：
3.8
作者：
Lin Chun-Nan;Chang Cheng-Hsiung;M. Arisawa;M. Shimizu;N. Morita
通讯作者：
Lin Chun-Nan;Chang Cheng-Hsiung;M. Arisawa;M. Shimizu;N. Morita
影响因子：
4.8
作者：
Anzai, Naohiko;Ichida, Kimiyoshi;Sakurai, Hiroyuki
通讯作者：
Sakurai, Hiroyuki
影响因子：
3.9
作者：
A. Wolman;M. Gionfriddo;Gregory A. Heindel;Paran Mukhija;S. Witkowski;A. Bommareddy;Adam L VanWert
通讯作者：
A. Wolman;M. Gionfriddo;Gregory A. Heindel;Paran Mukhija;S. Witkowski;A. Bommareddy;Adam L VanWert