title: Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor.
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-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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Mitin
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Von Moltke
authors.forename: Michael H
authors.initials: MH
authors.lastname: Court
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D013974:Thyroxine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013974:Thyroxine