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Thyroid hormones are transport substrates and transcriptional regulators of Organic Anion Transporting Polypeptide 2B1
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4479643
Author(s) Meyer zu Schwabedissen, Henriette E.; Ferreira, Celio; Schaefer, Anima M.; Oufir, Mouhssin; Seibert, Isabell; Hamburger, Matthias; Tirona, Rommel G.
Author(s) at UniBasel Ferreira, Celio
Schäfer, Anima Magdalena
Oufir, Mouhssin
Seibert, Isabell
Hamburger, Matthias
Meyer zu Schwabedissen, Henriette
Year 2018
Title Thyroid hormones are transport substrates and transcriptional regulators of Organic Anion Transporting Polypeptide 2B1
Journal Molecular Pharmacology
Volume 94
Number 1
Pages / Article-Number 700-712
Mesh terms Animals; Atorvastatin, pharmacology; Biological Transport, physiology; Caco-2 Cells; Cell Line; Cell Line, Tumor; Dogs; Drug Interactions, physiology; Estrone, pharmacology; Genes, Reporter, physiology; HeLa Cells; Hep G2 Cells; Humans; Intestinal Absorption, physiology; Madin Darby Canine Kidney Cells; Organic Anion Transporters, metabolism; Promoter Regions, Genetic, physiology; Thyroid Hormones, metabolism; Transcription, Genetic, physiology
Abstract Levothyroxine replacement therapy forms the cornerstone of hypothyroidism management. Variability in levothyroxine oral absorption may contribute to the well-recognized large interpatient differences in required dose. Moreover, levothyroxine-drug pharmacokinetic interactions are thought to be caused by altered oral bioavailability. Interestingly, little is known regarding the mechanisms contributing to levothyroxine absorption in the gastrointestinal tract. Here, we aimed to determine whether the intestinal drug uptake transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1) may be involved in facilitating intestinal absorption of thyroid hormones. We also explored whether thyroid hormones regulate OATP2B1 gene expression. In cultured MDCKII-OATP2B1 cells and in OATP2B1-transfected Caco-2 cells, thyroid hormones were found to inhibit OATP2B1-mediated uptake of estrone 3-sulfate. Competitive counter-flow experiments evaluating the influence on the cellular accumulation of estrone 3-sulfate in the steady-state, indicated that thyroid hormones were substrates of OATP2B1. Additional evidence that thyroid hormones were OATP2B1 substrates was provided by OATP2B1-dependent stimulation of thyroid hormone receptor activation in cell-based reporter assays. Bidirectional transport studies in intestinal Caco-2 cells showed net absorptive flux of thyroid hormones, which was attenuated by the presence of the OATP2B1 inhibitor, atorvastatin. In intestinal Caco-2 and LS180 cells, but not in liver Huh-7 or HepG2 cells, OATP2B1 expression was induced by treatment with thyroid hormones. Reporter genes assays revealed thyroid hormone receptor α-mediated transactivation of the SLCO2B1 1b and the SLCO2B1 1e promoters. We conclude that thyroid hormones are substrates and transcriptional regulators of OATP2B1. These insights provide a potential mechanistic basis for oral levothyroxine dose variability and drug interactions.
Publisher American Society for Pharmacology and Experimental Therapeutics
ISSN/ISBN 0026-895X ; 1521-0111
edoc-URL https://edoc.unibas.ch/65646/
Full Text on edoc No
Digital Object Identifier DOI 10.1124/mol.117.111161
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/29735582
ISI-Number WOS:000435118700004
Document type (ISI) Journal Article
 
   

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