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Efflux excretion of bisdemethoxycurcumin-O-glucuronide in UGT1A1-overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 (MRP1) as the glucuronide transporters.

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机构： [1]Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China [2]College of Pharmacy, Jinan University, Guangzhou, China [3]Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China [4]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development Ministry of P.R. China, Jinan University, Guangzhou, China [5]Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

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关键词： BDMC UGT1A1 glucuronidation efflux transporters HeLa cell

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Bisdemethoxycurcumin (BDMC) was a natural curcuminoid with many bioactivities present in turmeric (Curcuma longa L.). However, the disposition mechanisms of BDMC via uridine 5'-diphospho-glucuronosyltransferase (UGT) metabolism still remain unclear. Therefore, we aimed to determine the potential efflux transporters for the excretion of BDMC-O-glucuronide. Herein, chemical inhibition assays (Ko143, MK571, dipyridamole, and leukotriene C4) and biological inhibition experiments including stable knocked-down of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRPs) transporters were both performed in a HeLa cell line stably overexpressing UGT1A1 established previously. The results indicated that Ko143 (5 and 20 μM) caused a marked reduction in excretion rate (18.4-55.6%) and elevation of intracellular BDMC-O-glucuronide (28.8-48.1%), whereas MK-571 (5 and 20 μM) resulted in a significant decrease in excretion rate (6.2-61.6%) and increase of intracellular BDMC-O-glucuronide (maximal 27.1-32.6%). Furthermore, shRNA-mediated silencing of BCRP transporter led to a marked reduction in the excretion rate (21.1-36.9%) and an obvious elevation of intracellular glucuronide (24.9%). Similar results were observed when MRP1 was partially silenced. In addition, MRP3 and MRP4 silencing both displayed no obvious changes on the excretion rate and intracellular levels of glucuronide. In conclusion, chemical inhibition and gene silencing results both indicated that generated BDMC-O-glucoside were excreted primarily by the BCRP and MRP1 transporters. © 2018 BioFactors, 44(6):558-569, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

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出版当年[2017]版：

大类 | 2 区生物

小类 | 2 区内分泌学与代谢 3 区生化与分子生物学

最新[2025]版：

大类 | 3 区生物学

小类 | 3 区生化与分子生物学 4 区内分泌学与代谢

第一作者：

第一作者机构： [1]Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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通讯机构： [2]College of Pharmacy, Jinan University, Guangzhou, China [3]Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China [4]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development Ministry of P.R. China, Jinan University, Guangzhou, China [*1]College of Pharmacy, Jinan University, Guangzhou 510632, China

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Efflux excretion of bisdemethoxycurcumin-O-glucuronide in UGT1A1-overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 (MRP1) as the glucuronide transporters.

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