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

Timur Mitin, Lisa L. Von Moltke, Michael H. Court, David J. Greenblatt

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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-T4), triiodo-L-thyronine (L-T3), and rifampin. Results indicate that L-T4, L-T3, and rifampin can up-regulate the expression of P-gp mRNA and protein in LS180 cells, but only L-T4 and L-T 3 can produce the same effect in Caco-2 cells, which are relatively lacking in PXR. In addition, L-T4 and L-T3 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-T4 preparations in the older adult population, these results may be important for the clinical consideration of drug-drug interactions mediated by P-gp.

Original languageEnglish (US)
Pages (from-to)779-782
Number of pages4
JournalDrug Metabolism and Disposition
Volume32
Issue number8
DOIs
StatePublished - Aug 2004
Externally publishedYes

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P-Glycoprotein
Cytochrome P-450 CYP3A
Thyroxine
Up-Regulation
Rifampin
Thyronines
Cell Line
Messenger RNA
Caco-2 Cells
Xenobiotics
Regulator Genes
Cytoplasmic and Nuclear Receptors
Thyroid Hormones
Drug Interactions
Intestines
Prescriptions
Colon
Proteins
pregnane X receptor
Carcinoma

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor. / Mitin, Timur; Von Moltke, Lisa L.; Court, Michael H.; Greenblatt, David J.

In: Drug Metabolism and Disposition, Vol. 32, No. 8, 08.2004, p. 779-782.

Research output: Contribution to journalArticle

Mitin, Timur ; Von Moltke, Lisa L. ; Court, Michael H. ; Greenblatt, David J. / Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor. In: Drug Metabolism and Disposition. 2004 ; Vol. 32, No. 8. pp. 779-782.
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