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OATP1B3-1B7 (LST-3TM12) Is a Drug Transporter That Affects Endoplasmic Reticulum Access and the Metabolism of Ezetimibe
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4510236
Author(s) Malagnino, Vanessa; Duthaler, Urs; Seibert, Isabell; Krähenbühl, Stephan; Meyer Zu Schwabedissen, Henriette E.
Author(s) at UniBasel Meyer zu Schwabedissen, Henriette
Malagnino, Vanessa
Seibert, Isabell
Duthaler, Urs
Krähenbühl, Stephan
Year 2019
Title OATP1B3-1B7 (LST-3TM12) Is a Drug Transporter That Affects Endoplasmic Reticulum Access and the Metabolism of Ezetimibe
Journal Molecular Pharmacology
Volume 96
Number 2
Pages / Article-Number 128-137
Mesh terms Biological Transport; Catalytic Domain; Endoplasmic Reticulum, Smooth, chemistry; Ezetimibe, pharmacokinetics; Glucuronosyltransferase, chemistry; HeLa Cells; Humans; Intestine, Small, metabolism; Microsomes, Liver, metabolism; Organic Anion Transporters, metabolism; Solute Carrier Proteins, metabolism; Sulfobromophthalein, pharmacology
Abstract Drug transporters play a crucial role in pharmacokinetics. One subfamily of transporters with proven clinical relevance are the OATP1B transporters. Recently we identified a new member of the OATP1B family named OATP1B3-1B7 (LST-3TM12). This functional transporter is encoded by; SLCO1B3; and; SLCO1B7; OATP1B3-1B7 is expressed in hepatocytes and is located in the membrane of the smooth endoplasmic reticulum (SER). One aim of this study was to test whether OATP1B3-1B7 interacts with commercial drugs. First, we screened a selection of OATP1B substrates for inhibition of OATP1B3-1B7-mediated transport of dehydroepiandrosterone sulfate and identified several inhibitors. One such inhibitor was ezetimibe, which not only inhibited OATP1B3-1B7 but is also a substrate, as its cellular content was significantly increased in cells heterologously expressing the transporter. In humans, ezetimibe is extensively metabolized by hepatic and intestinal uridine-5'-diphospho-glucuronosyltransferases (UGTs), the catalytic site of which is located within the SER lumen. After verification of OATP1B3-1B7 expression in the small intestine, we determined in microsomes whether SER access can be modulated by inhibitors of OATP1B3-1B7. We were able to show that these compounds significantly reduced accumulation in small intestinal and hepatic microsomes, which influenced the rate of ezetimibe; β; -D-glucuronide formation as determined in microsomes treated with bromsulphthalein. Notably, this molecule not only inhibits the herein reported transporter but also other transport systems. In conclusion, we report that multiple drugs interact with OATP1B3-1B7; for ezetimibe, we were able to show that SER access and metabolism is significantly reduced by bromsulphthalein, which is an inhibitor of OATP1B3-1B7. SIGNIFICANCE STATEMENT: OATP1B3-1B3 (LST-3TM12) is a transporter that has yet to be fully characterized. We provide valuable insight into the interaction potential of this transporter with several marketed drugs. Ezetimibe, which interacted with OATP1B3-1B7, is highly metabolized by uridine-5'-diphospho-glucuronosyltransferases (UGTs), whose catalytic site is located within the smooth endoplasmic reticulum (SER) lumen. Through microsomal assays with ezetimibe and the transport inhibitor bromsulphthalein we investigated the interdependence of SER access and the glucuronidation rate of ezetimibe. These findings led us to the hypothesis that access or exit of drugs to the SER is orchestrated by SER transporters such as OATP1B3-1B7.
Publisher American Society for Pharmacology and Experimental Therapeutics
ISSN/ISBN 0026-895X ; 1521-0111
edoc-URL https://edoc.unibas.ch/71555/
Full Text on edoc No
Digital Object Identifier DOI 10.1124/mol.118.114934
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/31127008
ISI-Number WOS:000476655900002
Document type (ISI) Journal Article
 
   

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19/04/2024