Thyroid hormone regulates the expression and function of P-glycoprotein in Caco-2 cells

Purpose. In patients with thyroid disorders, abnormalities in the pharmacokinetics of various drugs including digoxin, a substrate of P-glycoprotein (Pgp) which plays a crucial role in drug absorption and disposition, have been reported. In this study, we examined the effect of 3,5,3'-L-triiodothyronine (T-3) on the function and expression of Pgp using the human intestinal epithelial cell line Caco-2. Materials and Methods. The effect of T-3 on the expression of Pgp and MDR1 mRNA was assessed by Western blotting and competitive polymerase chain reaction, respectively. Digoxin uptake and transport by Pgp was assessed using Caco-2 cell monolayers. Results. The expression of MDR1 mRNA was increased by T-3 treatment in a concentration-dependent manner. Pgp expression was also increased by 100 nM T-3, whereas it decreased on depletion of T-3. The amount of [H-3]digoxin accumulated in Caco-2 cell monolayers treated with T-3 was diminished significantly compared with that in control cells. In addition, the basal-to-apical transcellular transport of [H-3]digoxin was accelerated by T-3 treatment. Conclusions. These results indicate that T-3 regulates the expression and function of Pgp. It is possible that changes in Pgp expression alter the pharmacokinetics of Pgp substrates in patients with thyroid disorders.