摘要
目的研究不同药性中药成分对尿酸重吸收转运体尿酸转运蛋白1(URAT1)和有机阴离子转运蛋白4(OAT4)的抑制作用及对急性高尿酸血症小鼠尿酸水平的影响。方法应用OAT4、URAT1过表达单克隆细胞株(MDCK-hOAT4、HEK293-hURAT1),检测各药性中药单体对OAT4、URAT1的抑制作用及半数抑制浓度(IC50);运用黄嘌呤联合氧嗪酸钾制备急性高尿酸血症小鼠模型,研究原儿茶酸、甘草素、异甘草素对急性高尿酸血症小鼠血清尿酸的影响。结果苦味药中的川陈皮素,甘味药中的甘草素、异甘草素、甘草查耳酮A对OAT4抑制作用较强,IC50分别是0.556、18.40、6.831、6.825μmol/L。酸味药中的原儿茶酸、甘味药中的甘草素对URAT1具有较强的抑制作用,IC50分别是7.709、14.540μmol/L。甘草素能显著降低急性高尿酸血症小鼠的血尿酸水平,增加尿酸排泄量,降低血清肌酐、尿素氮的含量。结论川陈皮素、甘草素、异甘草素、甘草查耳酮A对OAT4具有较强的抑制作用,原儿茶酸、甘草素对URAT1具有较强抑制作用。甘草素能显著降低急性高尿酸血症小鼠血尿酸水平,其作用机制可能是抑制OAT4、URAT1对尿酸的重吸收,并具有一定的肾脏保护作用。
Objective To study the effects of Chinese herb ingredients with different properties on transporters(URAT1 and OAT4)involved in renal urate reabsorption and serum uric acid level in acute hyperuricemia mice. Methods The OAT4, URAT1-overexpressed monoclonal cell line(MDCK-hOAT4, HEK293-hURAT1) was constructed. The inhibition effect and the half maximal inhibitory concentration(IC50) of different ingredients to transport activity of OAT4 and URAT1 mediating 14 C-uric acid were determined. The effects of protocatechuic, liquiritigenin and isoliquiritigenin on serum uric acid levels in acute hyperuricemia mice were studied by the acute hyperuricemia mice induced by potassium oxonate and xanthine. Results The results indicated that nobiletin,liquiritigenin, isoliquiritigenin, licochalcone A with bitter flavor showed strong inhibition to OAT4. The IC50 of nobiletin,liquiritigenin, isoliquiritigenin, and licochalcone A on OAT4 were 0.556 μmol/L, 18.40 μmol/L, 6.831 μmol/L, and 6.825 μmol/L,respectively. Protocatechuic acid and liquiritigenin showed strong inhibition to URAT1 with IC50 of 7.709 μmol/L and 14.54 μmol/L,respectively. Liquiritigenin can significantly reduce the level of serum uric acid of acute hyperuricemia mice, increase the excretion of uric acid, and reduce the level of serum creatinine and blood urea nitrogen. Conclusion Nobiletin, liquiritigenin, isoliquiritigenin and licochalcone A can inhibit the transport activity of OAT4, while protocatechuic acid and liquiritigenin can inhibit the transport activity of URAT1. Liquiritigenin can significantly reduce the level of serum uric acid in acute hyperuricemia mice and protect kidney, the mechanism of which may be associated with the decreasing reabsorption of uric acid by inhibiting the activity of URAT1 and OAT4.
引文
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