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

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.