TY - JOUR T1 - LEVOTHYROXINE UP-REGULATES P-GLYCOPROTEIN INDEPENDENT OF THE PREGNANE X RECEPTOR JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 779 LP - 782 DO - 10.1124/dmd.32.8.779 VL - 32 IS - 8 AU - Tim Mitin AU - Lisa L. von Moltke AU - Michael H. Court AU - David J. Greenblatt Y1 - 2004/08/01 UR - http://dmd.aspetjournals.org/content/32/8/779.abstract N2 - 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 upregulate the expression of P-gp mRNA and protein in LS180 cells, but only l-T4 and l-T3 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. The American Society for Pharmacology and Experimental Therapeutics ER -