Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor

Tim Mitin; Lisa L Von Moltke; Michael H Court; David J Greenblatt

doi:10.1124/dmd.32.8.779

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Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor

Journal article

Peer reviewed

Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor

Tim Mitin, Lisa L Von Moltke, Michael H Court and David J Greenblatt

Drug metabolism and disposition, Vol.32(8), pp.779-782

08/2004

DOI: https://doi.org/10.1124/dmd.32.8.779

Handle:

https://hdl.handle.net/2376/107033

PMID: 15258100

Abstract

Caco-2 Cells

ATP Binding Cassette Transporter, Subfamily B, Member 1 - biosynthesis

Humans

Receptors, Cytoplasmic and Nuclear - genetics

Receptors, Cytoplasmic and Nuclear - biosynthesis

ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics

Dose-Response Relationship, Drug

Up-Regulation - drug effects

Receptors, Steroid - biosynthesis

Receptors, Steroid - genetics

Up-Regulation - physiology

Pregnane X Receptor

Thyroxine - pharmacology

P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) constitute a physiologic barrier in the intestine for many of the same substrates. Their expression can be influenced by nuclear receptor NR1I2 (pregnane X receptor; PXR), which acts as a receptor for various endobiotics and xenobiotics. However, P-gp and CYP3A4 are not identical in anatomic localization, suggesting unique as well as shared regulatory mechanisms of gene expression. We used established human colon carcinoma cell lines (LS180 and Caco-2) and measured mRNA and protein levels in cells after exposures to levothyroxine (L-T(4)), triiodo-L-thyronine (L-T(3)), and rifampin. Results indicate that L-T(4), L-T(3), and rifampin can upregulate the expression of P-gp mRNA and protein in LS180 cells, but only L-T(4) and L-T(3) can produce the same effect in Caco-2 cells, which are relatively lacking in PXR. In addition, L-T(4) and L-T(3) did not affect the expression of CYP3A4 in either cell line. We conclude that P-gp, but not CYP3A4, can be up-regulated by thyroid hormones in vitro by a PXR-independent mechanism. Considering the widespread prescription use of L-T(4) preparations in the older adult population, these results may be important for the clinical consideration of drug-drug interactions mediated by P-gp.

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Title: Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor
Creators: Tim Mitin - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
Lisa L Von Moltke
Michael H Court
David J Greenblatt
Publication Details: Drug metabolism and disposition, Vol.32(8), pp.779-782
Academic Unit: Veterinary Clinical Sciences, Department of
Publisher: United States
Grant note: DA-13834 / NIDA NIH HHS GM-61834 / NIGMS NIH HHS DA-05258 / NIDA NIH HHS AG-17880 / NIA NIH HHS DK/AI-58496 / NIDDK NIH HHS RR-00054 / NCRR NIH HHS AT-01381 / NCCIH NIH HHS DA-13209 / NIDA NIH HHS MH-58435 / NIMH NIH HHS
Identifiers: 99900546867401842
Language: English
Resource Type: Journal article

Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor

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