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 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.
Footnotes
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This work was supported in part by Grants MH-58435, GM-61834, DA-05258, DA-13209, DK/AI-58496, DA-13834, AG-17880, AT-01381, and RR-00054 from the U.S. Department of Health and Human Services.
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ABBREVIATIONS: P-gp, p-glycoprotein; CYP3A4, cytochrome P450 3A4; PXR, pregnane X receptor (nuclear receptor NR1I2); l-T4, levothyroxine; l-T3, 3,3′,5-triiodo-l-thyronine; TR, thyroid receptor; VDR, vitamin D receptor; RXR, retinoid X receptor, Vit D3, 1α,25-dihydroxyvitamin D3; DR, direct repeat; RAR, retinoic acid receptor; ABCB1, ATP-binding cassette protein B1; kb, kilobase(s); HPLC, high-performance liquid chromatography; PCR, polymerase chain reaction.
- Received February 19, 2004.
- Accepted April 26, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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