title: Transcriptional Regulation of Human UDP-Glucuronosyltransferase 2B10 by Farnesoid X Receptor in Human Hepatoma HepG2 Cells.
abstract: Little is known about transcriptional regulators of UDP-glucuronosyltransferase 2B10 (UGT2B10), an enzyme known to glucuronidate many chemicals and drugs such as nicotine and tricyclic antidepressants. Here, we uncovered that UGT2B10 was transcriptionally regulated by farnesoid X receptor (FXR), the bile acid sensing nuclear receptor. GW4064 and chenodeoxycholic acid (two specific FXR agonists) treatment of HepG2 cells led to a significant increase in the mRNA level of UGT2B10. The treated cells also showed enhanced glucuronidation activities toward amitriptyline (an UGT2B10 probe substrate). In reporter gene assays, the extent of UGT2B10 activation by the FXR agonists was positively correlated with the amount of cotransfected FXR. Consistently, knockdown of FXR by shRNA attenuated the induction effect on UGT2B10 expression. Furthermore, a combination of electrophoretic mobility shift assay and chromatin immunoprecipitation showed that the FXR receptor trans-activated UGT2B10 through its specific binding to the -209- to -197-bp region (an IR1 element) of the UGT2B10 promoter. In summary, our results for the first time established FXR as a transcriptional regulator of human UGT2B10.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Danyi
authors.initials: D
authors.lastname: Lu
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Lianxia
authors.initials: L
authors.lastname: Guo
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Baojian
authors.identifier: 0000-0003-4629-5142
authors.initials: B
authors.lastname: Wu
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D014453:Glucuronosyltransferase; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D000099150:Receptor, Farnesoid X-Activated; C552162:UGT2B10 protein, human; C412815:GW 4064
keywords: FXR; UGT2B10; glucuronidation; transcriptional regulation