Sulfation disposition of liquiritigenin in SULT1A3 overexpressing HEK293 cells: The role of breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4) in sulfate efflux of liquiritigenin

被引：6
作者：
Liu, Tong [1 ]
Zhang, Xiaojing [1 ]
Zhang, Yidan [1 ]
Hou, Jiuzhou [1 ]
Fang, Dong [1 ]
Sun, Hua [1 ]
Li, Qin [1 ]
Xie, Songqiang [2 ]
机构：
[1] Henan Univ, Sch Pharm, Inst Innovat Drug Design & Evaluat, N Jinming Ave, Kaifeng 475004, Henan, Peoples R China
[2] Henan Univ, Sch Pharm, Inst Chem Biol, N Jinming Ave, Kaifeng 475004, Henan, Peoples R China
来源：
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES | 2018年 / 124卷
基金：
中国博士后科学基金; 中国国家自然科学基金;
关键词：
Liquiritigenin; Sulfotransferase; Sulfonation; Efflux transporter; HEK293; cells; HUMAN CYTOSOLIC SULFOTRANSFERASES; UGT1A1-OVEREXPRESSING HELA-CELLS; RATS LOW BIOAVAILABILITY; KIDNEY; 293; CELLS; UDP-GLUCURONOSYLTRANSFERASES; REDUCED GLUCURONIDATION; TRANSPORT INTERPLAY; DIETARY FLAVONOIDS; P-GLYCOPROTEIN; CACO-2;
D O I：
10.1016/j.ejps.2018.08.041
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
This study aimed to investigate the cellular disposition of liquiritigenin via the sulfonation pathway and the role of efflux transporters in liquiritigenin sulfate excretion. The sulfonation disposition of liquiritigenin was investigated using SULT1A3 overexpressed HEK293 cells (HEK-SULT1A3 cells). Liquiritigenin generated one mono-sulfate metabolite (7-0-sulfate) in HEK-SULT1A3 cell lysate. And the sulfonation followed the Michaelis-Menten kinetic (V-max = 0.84 nmol/min/mg and K-m = 7.12 mu M). Expectedly, recombinant SULT1A3 (hSULT1A3) showed a highly similar kinetic profile with cell lysate. Furthermore, 7-0-sulfate was rapidly generated and excreted in HEK-SULT1A3 cells. Ko143 (a BCRP-selective inhibitor) at 20 mu M significantly decreased the excretion rate of liquiritigenin sulfate ( > 42.5%, p < 0.001). Moreover, the pan-MRPs inhibitor MK-571 at 20 mu M essentially abolished the liquiritigenin sulfate effluxion, resulting in the marked reduction of excretion rate ( > 97.4%, p < 0.001). Furthermore, knockdown of BCRP led to moderate reduction in sulfate excretion (15.9%-16.9%, p < 0.05). Silencing of MRP4 caused significant decreased in sulfate excretion (20.2%-32.5%, p < 0.01). In conclusion, one sulfate metabolite was generated from liquiritigenin in HEK-SULT1A3 cells. BCRP and MRP4 should be the key factors for the cellular excretion of liquiritigenin sulfate.
引用
收藏
页码：228 / 239
页数：12
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