C Di Cosmo1, G De Marco2, P Agretti3, E Ferrarini2, A Dimida2, P Falcetta2, S Benvenga4, P Vitti2, M Tonacchera2. 1. Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Pisa, via Paradisa 2, 56124, Pisa, Italy. katiadicosmo@yahoo.it. 2. Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Pisa, via Paradisa 2, 56124, Pisa, Italy. 3. Laboratory of Chemistry and Endocrinology, University Hospital of Pisa, Pisa, Italy. 4. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Abstract
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 T3 transport. METHODS: [125I]T3 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 T3 uptake at 10 μM; hydrocortisone reduced T3 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 T3 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 T3 uptake at 0.1-10 μM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.
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 T3 transport. METHODS: [125I]T3 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 T3 uptake at 10 μM; hydrocortisone reduced T3 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 T3 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 T3 uptake at 0.1-10 μM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.
Authors: Edith C H Friesema; Theo J Visser; Anke J Borgers; Andries Kalsbeek; Dick F Swaab; Eric Fliers; Anneke Alkemade Journal: Eur J Endocrinol Date: 2012-06-21 Impact factor: 6.664
Authors: Edith C H Friesema; Annette Grueters; Heike Biebermann; Heiko Krude; Arpad von Moers; Maarten Reeser; Timothy G Barrett; Edna E Mancilla; Johan Svensson; Monique H A Kester; George G J M Kuiper; Sahila Balkassmi; André G Uitterlinden; Josef Koehrle; Patrice Rodien; Andrew P Halestrap; Theo J Visser Journal: Lancet Date: 2004 Oct 16-22 Impact factor: 79.321
Authors: Alexandra M Dumitrescu; Xiao-Hui Liao; Thomas B Best; Knut Brockmann; Samuel Refetoff Journal: Am J Hum Genet Date: 2003-12-05 Impact factor: 11.025
Authors: Lori M Roberts; Kathleen Woodford; Mei Zhou; Deborah S Black; Jill E Haggerty; Emily H Tate; Kent K Grindstaff; Wondwessen Mengesha; Chandrasekaran Raman; Noa Zerangue Journal: Endocrinology Date: 2008-08-07 Impact factor: 4.736
Authors: Edith C H Friesema; Sumita Ganguly; Amal Abdalla; Jocelyn E Manning Fox; Andrew P Halestrap; Theo J Visser Journal: J Biol Chem Date: 2003-07-18 Impact factor: 5.157
Authors: Edith C H Friesema; Jurgen Jansen; Jan-Willem Jachtenberg; W Edward Visser; Monique H A Kester; Theo J Visser Journal: Mol Endocrinol Date: 2008-03-12