The Efflux Mechanism of Fraxetin-O-Glucuronides in UGT1A9-Transfected HeLa Cells: Identification of Multidrug Resistance-Associated Proteins 3 and 4 (MRP3/4) as the Important Contributors.
机构：[1]Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,[2]Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China,[3]College of Pharmacy, Jinan University, Guangzhou, China,[4]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China,[5]Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Fraxetin, a natural compound present in many dietary supplements and herbs, is useful in the treatment of acute bacillary dysentery and type 2 diabetes. Previously, several metabolic studies have revealed extensive first-pass metabolism causing formation of fraxetin-O-glucuronides (G1 and G2), resulting in poor bioavailability of fraxetin. Active transport processes play an important role in the excretion of fraxetin-O-glucuronides. Nevertheless, the transporters involved are yet to be elucidated. In this study, we aimed to determine the active efflux transporters, including breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), involved in the excretion of fraxetin-O-glucuronides. A chemical inhibitor, MK571 (5 and 20 μM), a pan-MRP inhibitor, led to a significant decrease in excreted G1 (maximal 59.1%) and G2 levels (maximal 42.4%), whereas Ko143 (5 and 20 μM), a selective BCRP inhibitor, caused moderate downregulation of excreted G1 (maximal 29.4%) and G2 (maximal 28.5%). Furthermore, MRP3 silencing resulted in a marked decrease of excretion rates (by 29.1% for G1 and by 21.1% for G2) and of fraction metabolized (fmet; by 24.1% for G1 and by 18.6% for G2). Similar results, i.e., a significant reduction in excretion rates (by 34.8% for G1 and by 32.3% for G2) and in fmet (by 22.7% for G1 and by 23.1% for G2) were obtained when MRP4 was partially silenced. No obvious modifications in the excretion rates, intracellular levels, and fmet values of glucuronides were observed after short hairpin RNA (shRNA)-mediated silencing of transporters BCRP and MRP1. Taken together, our results indicate that MRP3 and MRP4 contribute more to the excretion of fraxetin-O-glucuronides than the other transporters do.
基金：
This work was supported byNationalMajor Scientific Program of
Introducing Talents of Discipline to Universities (B13038), State
Key Program of National Natural Science Foundation of China
(81630097), and Hospital Youth Foundation of the First Affiliated
Hospital of Zhengzhou University (YNQN2017200).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|2 区医学
小类|2 区药学
最新[2025]版：
大类|3 区医学
小类|3 区药学
第一作者：
第一作者机构：[1]Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,[2]Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China,
通讯作者：
通讯机构：[1]Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,[2]Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China,[3]College of Pharmacy, Jinan University, Guangzhou, China,[4]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China,
推荐引用方式(GB/T 7714)：
Zifei Qin,Beibei Zhang,Jing Yang,et al.The Efflux Mechanism of Fraxetin-O-Glucuronides in UGT1A9-Transfected HeLa Cells: Identification of Multidrug Resistance-Associated Proteins 3 and 4 (MRP3/4) as the Important Contributors.[J].Frontiers in pharmacology.2019,10:496.doi:10.3389/fphar.2019.00496.
APA：
Zifei Qin,Beibei Zhang,Jing Yang,Shishi Li,Jinjin Xu...&Xinsheng Yao.(2019).The Efflux Mechanism of Fraxetin-O-Glucuronides in UGT1A9-Transfected HeLa Cells: Identification of Multidrug Resistance-Associated Proteins 3 and 4 (MRP3/4) as the Important Contributors..Frontiers in pharmacology,10,
MLA：
Zifei Qin,et al."The Efflux Mechanism of Fraxetin-O-Glucuronides in UGT1A9-Transfected HeLa Cells: Identification of Multidrug Resistance-Associated Proteins 3 and 4 (MRP3/4) as the Important Contributors.".Frontiers in pharmacology 10.(2019):496
