Tianjin State Key Laboratory of Modern Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
J Ethnopharmacol. 2018 Mar 25;214:29-36. doi: 10.1016/j.jep.2017.12.004. Epub 2017 Dec 9.
Dioscin, a spirostane glycoside, the rhizoma of Dioscorea septemloba (Diocoreacea) is used for diuresis, rheumatism, and joints pain. Given the poor solubility and stability of Dioscin, we proposed a hypothesis that Dioscin's metabolite(s) are the active substance(s) in vivo to contribute to the reducing effects on serum uric acid levels.
The aim of this study is to identify the active metabolite(s) of Dioscin in vivo and to explore the mechanism of its antihyperuricemic activity.
After oral administration of Dioscin in potassium oxonate (PO) induced hyperuricemia rats and adenine-PO induced hyperuricemia mice models, serum uric acid and creatinine levels, clearance of uric acid and creatinine, fractional excretion of uric acid, and renal pathological lesions were determined were used to evaluate the antihyperuricemic effects. Renal glucose transporter-9 (GLUT-9) and organic anion transporter-1 (OAT-1) expressions were analyzed by western blotting method. Renal uric acid excretion was evaluated using stably urate transporter-1 (URAT-1) transfected human epithelial kidney cell line. Intestinal uric acid excretion was evaluated by measuring the transcellular transport of uric acid in HCT116 cells.
In hyperuricemia rats, both 25 and 50mg/kg of oral Dioscin decreased serum uric acid levels over 4h. In the hyperuricemia mice, two weeks treatment of Dioscin significantly decreased serum uric acid and creatinine levels, increased clearance of uric acid and creatinine, increased fractional excretion of uric acid, and reduced renal pathological lesions caused by hyperuricemia. In addition, renal GLUT -9 was significantly down-regulated and OAT-1 was up-regulated in Dioscin treated hyperuricemia mice. Dioscin's metabolite Tigogenin significantly inhibited uric acid re-absorption via URAT1 from 10 to 100μM. Diosgenin and Tigogenin increased uric acid excretion via ATP binding cassette subfamily G member 2 (ABCG2).
Decreasing effect of Dioscin on serum uric acid level and enhancing effect on urate excretion were confirmed in hyperuricemia animal models. Tigogenin, a metabolite of Dioscin, was identified as an active substance with antihyperuricemic activity in vivo, through inhibition of URAT1 and promotion of ABCG2.
薯蓣皂苷，一种螺旋甾烷糖苷，是薯蓣科薯蓣属植物的根茎，用于利尿、风湿和关节疼痛。鉴于薯蓣皂苷的溶解度和稳定性较差，我们提出了一个假设，即薯蓣皂苷的代谢物是体内的活性物质，有助于降低血清尿酸水平。
本研究旨在鉴定薯蓣皂苷在体内的活性代谢物，并探讨其抗高尿酸血症的作用机制。
在氧嗪酸钾（PO）诱导的高尿酸血症大鼠和腺嘌呤-PO 诱导的高尿酸血症小鼠模型中口服薯蓣皂苷后，测定血清尿酸和肌酐水平、尿酸和肌酐清除率、尿酸排泄分数以及肾脏病理损伤，以评价抗高尿酸血症作用。采用 Western blot 法分析肾脏葡萄糖转运蛋白-9（GLUT-9）和有机阴离子转运蛋白-1（OAT-1）的表达。采用稳定转染尿酸盐转运体-1（URAT-1）的人肾小管上皮细胞系评估肾脏尿酸排泄。通过测定 HCT116 细胞中尿酸的跨细胞转运来评估肠道尿酸排泄。
在高尿酸血症大鼠中，口服 25 和 50mg/kg 的薯蓣皂苷可在 4 小时内降低血清尿酸水平。在高尿酸血症小鼠中，薯蓣皂苷治疗两周可显著降低血清尿酸和肌酐水平，增加尿酸和肌酐清除率，增加尿酸排泄分数，并减轻高尿酸血症引起的肾脏病理损伤。此外，薯蓣皂苷治疗的高尿酸血症小鼠肾脏 GLUT-9 显著下调，OAT-1 上调。薯蓣皂苷的代谢产物替告皂苷元在 10 至 100μM 时可显著抑制 URAT1 介导的尿酸重吸收。薯蓣皂苷元和替告皂苷元通过三磷酸腺苷结合盒亚家族 G 成员 2（ABCG2）增加尿酸排泄。
在高尿酸血症动物模型中证实了薯蓣皂苷降低血清尿酸水平和增强尿酸排泄的作用。替告皂苷元，薯蓣皂苷的代谢产物，被鉴定为体内具有抗高尿酸血症活性的活性物质，通过抑制 URAT1 和促进 ABCG2。
