Screening for drugs potentially interfering with MCT8-mediated T 3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity

Background Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. Aim This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T 3 transport. Methods [ 125 I]T 3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and l -carnitine. The mode of inhibition was also determined. Results Dexamethasone significantly inhibited T 3 uptake at 10 μM; hydrocortisone reduced T 3 uptake only at high concentrations, i.e. at 500 and 1000 μM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T 3 uptake by MCT8 only at the highest concentrations used (44% at 50 μM and 68% at 100 μM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T 3 uptake at 0.1–10 μM. l -Carnitine inhibited T 3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T 3 uptake did not affect T 3 release. Conclusion This study shows a novel effect of some common drugs, which is inhibition of T 3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.