Stable knock-down of efflux transporters leads to reduced glucuronidation in UGT1A1-overexpressing HeLa cells: the evidence for glucuronidation-transport interplay

Molecular Pharmaceutics
Xingwang ZhangBaojian Wu

Abstract

Efflux of glucuronide is facilitated by the membrane transporters including BCRP and MRPs. In this study, we aimed to determine the effects of transporter expression on glucuronide efflux and cellular glucuronidation. Single efflux transporter (i.e., BCRP, MRP1, MRP3, or MRP4) was stably knocked-down in UGT1A1-overexpressing HeLa cells. Knock-down of transporters was performed by stable transfection of short-hairpin RNA (shRNA) using lentiviral vectors. Glucuronidation and glucuronide transport in the cells were characterized using three different aglycones (i.e., genistein, apigenin, and emodin) with distinct metabolic activities. BCRP knock-down resulted in significant reductions in excretion of glucuronides (42.9% for genistein glucuronide (GG), 21.1% for apigenin glucuronide (AG) , and 33.7% for emodin glucuronide (EG); p < 0.01) and in cellular glucuronidation (38.3% for genistein, 38.6% for apigenin, and 34.7% for emodin; p < 0.01). Knock-down of a MRP transporter led to substantial decreases in excretion of GG (32.3% for MRP1, 36.7% for MRP3, and 36.6% for MRP4; p < 0.01) and AG (59.3% for MRP1, 24.7% for MRP3, and 34.1% for MRP4; p < 0.01). Also, cellular glucuronidation of genistein (38.3% for MRP1, 32.3% for MRP3, and...Continue Reading

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Citations

Mar 8, 2017·Drug Metabolism Reviews·Guangyi YangMing Hu
Feb 14, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Chunli QiBaojian Wu
Mar 31, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jiamei ChenZhongqiu Liu
Dec 15, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tianpeng ZhangBaojian Wu
Jun 18, 2019·Drug Metabolism Reviews·Himanshu VermaOm Silakari
Jun 22, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mengjing ZhaoBaojian Wu
Jul 10, 2018·Current Medicinal Chemistry·Ana María González-ParamásCelestino Santos-Buelga
Dec 26, 2018·Expert Opinion on Drug Metabolism & Toxicology·Liping WangZhongqiu Liu
Jul 3, 2020·Journal of Pharmaceutical Analysis·Ya-Di ZhuGuang-Bo Ge

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