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Disposition of mianserin and cyclizine in UGT2B10-overexpressing HEK293 cells: Identification of UGT2B10 as a novel N-glucosidation enzyme and BCRP as an N-glucoside transporter.

  • Lu, Danyi1
  • Dong, Dong2
  • Xie, Qian1
  • Li, Zhijie2
  • Wu, Baojian3
  • 1 College of Pharmacy, Jinan University.
  • 2 School of Medicine, Jinan University.
  • 3 College of Pharmacy, Jinan University; [email protected]
Published Article
Drug metabolism and disposition: the biological fate of chemicals
Publication Date
Apr 24, 2018
DOI: 10.1124/dmd.118.080804
PMID: 29691239


UDP-glucuronosyltransferases (UGTs) play an important role in metabolism and detoxification of amine-containing chemicals. However, the disposition mechanisms for amines via UGT metabolism are not fully clear. Here we aim to investigate a potential role of UGT2B10 in N-glucosidation, and to determine the transporters for excretion of N-glucosides. We first established a HEK293 cell line stably overexpressing 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 biological inhibition (using specific shRNA) of BCRP resulted in a significant reduction in efflux of N-glucuronide. Similar results were observed when MRP4 was inhibited. Furthermore, inhibition of BCRP led to increased intracellular N-glucoside, whereas inhibition of MRP4 caused no changes in disposition of N-glucosides. The data overall indicated that BCRP not MRP4 was responsible for excretion of N-glucosides, whereas both BCRP and MRP4 contributed to excretion of N-glucuronides. Interestingly, down-regulation 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 a N-glucosidation enzyme. Generated N-glucosides were excreted primarily by the BCRP transporter.

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