Disposition of Mianserin and Cyclizine in UGT2B10-Overexpressing Human Embryonic Kidney 293 Cells: Identification of UGT2B10 as a Novel N-Glucosidation Enzyme and Breast Cancer Resistance Protein as an N-Glucoside Transporter

	Disposition of Mianserin and Cyclizine in UGT2B10-Overexpressing Human Embryonic Kidney 293 Cells: Identification of UGT2B10 as a Novel N-Glucosidation Enzyme and Breast Cancer Resistance Protein as an N-Glucoside Transporter
	Danyi Lu; Dong Dong; Qian Xie; Zhijie Li; Baojian Wu
刊名	Drug Metabolism and Disposition
	2018
文献子类	期刊论文
英文摘要	UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and detoxification of amine-containing chemicals; however, the disposition mechanisms for amines via UGT metabolism are not fully clear. We aimed to investigate a potential role of UGT2B10 in N-glucosidation and to determine the transporters for the excretion of N-glucosides. We first established a human embryonic kidney cell line 293 (HEK293) that stably overexpressed UGT2B10. Incubation of mianserin or cyclizine with the cells generated one N-glucuronide and one N-glucoside. Chemical inhibition (using specific chemical inhibitor Ko143) and biologic inhibition [using specific short hairpin RNA of breast cancer resistance protein (BCRP)] resulted in a significant reduction in efflux of N-glucuronide. Similar results were observed when multidrug resistance-associated protein (MRP4) was inhibited. Furthermore, inhibition of BCRP led to increased intracellular N-glucoside, whereas inhibition of MRP4 caused no changes in disposition of N-glucoside. Overall, the data indicated that BCRP, not MRP4, was responsible for the excretion of N-glucosides, whereas both BCRP and MRP4 contributed to excretion of N-glucuronides. Interestingly, downregulation of N-glucuronidation led to increased N-glucosidation in the cells, supporting the glucosidation as a potential complementary pathway for conventional glucuronidation. In conclusion, UGT2B10 was for the first time identified as an N-glucosidation enzyme. Generated N-glucosides were excreted primarily by the BCRP transporter.
URL标识	查看原文
语种	英语
内容类型	期刊论文
源URL	[http://ir.siat.ac.cn:8080/handle/172644/14609]
专题	深圳先进技术研究院_医药所
推荐引用方式 GB/T 7714	Danyi Lu,Dong Dong,Qian Xie,et al. Disposition of Mianserin and Cyclizine in UGT2B10-Overexpressing Human Embryonic Kidney 293 Cells: Identification of UGT2B10 as a Novel N-Glucosidation Enzyme and Breast Cancer Resistance Protein as an N-Glucoside Transporter[J]. Drug Metabolism and Disposition,2018.
APA	Danyi Lu,Dong Dong,Qian Xie,Zhijie Li,&Baojian Wu.(2018).Disposition of Mianserin and Cyclizine in UGT2B10-Overexpressing Human Embryonic Kidney 293 Cells: Identification of UGT2B10 as a Novel N-Glucosidation Enzyme and Breast Cancer Resistance Protein as an N-Glucoside Transporter.Drug Metabolism and Disposition.
MLA	Danyi Lu,et al."Disposition of Mianserin and Cyclizine in UGT2B10-Overexpressing Human Embryonic Kidney 293 Cells: Identification of UGT2B10 as a Novel N-Glucosidation Enzyme and Breast Cancer Resistance Protein as an N-Glucoside Transporter".Drug Metabolism and Disposition (2018).