Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Phytomedicine. 2021 Jan;80:153374. doi: 10.1016/j.phymed.2020.153374. Epub 2020 Oct 9.
Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities.
To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo.
We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and C-urate uptake assays. To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds.
BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC values of 30.17 ± 8.68 μM and 31.56 ± 1.37 μM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1.
These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity.
尿酸排泄不足和/或尿酸（UA）生成过多是导致高尿酸血症的主要原因。黄芩素（BAL）广泛存在于膳食植物中，具有广泛的生物学活性，包括抗氧化、抗炎和降压作用。
在体外和体内研究 BAL 的抗高尿酸血症作用及其机制。
通过电生理实验和 C-尿酸摄取测定，研究 BAL 对 GLUT9 和 URAT1 的抑制作用。为了评估 BAL 对血清和尿液 UA、GLUT9 和 URAT1 的表达以及黄嘌呤氧化酶（XOD）活性的影响，我们通过注射氧嗪酸钾（PO）建立了小鼠高尿酸血症模型。基于同源建模的分子对接分析用于解释 BAL 相对于其他测试化合物的主要功效。
BAL 呈剂量依赖性地非竞争性抑制 GLUT9 和 URAT1，IC 值分别为 30.17±8.68 μM 和 31.56±1.37 μM。BAL（200mg/kg）可显著降低 PO 诱导的高尿酸血症小鼠的血清 UA 并增强肾脏尿酸排泄。此外，肾脏中 GLUT9 和 URAT1 的表达下调，血清和肝脏中的 XOD 活性受到抑制。对接分析表明，BAL 与 GLUT9 的 Trp336、Asp462、Tyr71 和 Gln328 以及 URAT1 的 Ser35 和 Phe241 强力相互作用。
这些结果表明，BAL 通过促进肾脏 UA 排泄和抑制血清 UA 生成发挥强大的抗高尿酸血症作用。因此，我们提出 BAL 可能因其多靶点抑制活性而成为预防高尿酸血症的一种有前途的治疗方法。
