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Amiodarone Inhibits Thyroidal Iodide Transport in Vitro by a Cyclic Adenosine 5'-Monophosphate- and Iodine-Independent Mechanism

Department of Medical Chemistry and Cell Biology (S.T., F.L., M.N.), Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, 405 30 Göteborg, Sweden; Departments of Radiation Physics (C.J.) and Medicine (E.N.), Sahlgrenska University Hospital, 41345 Göteborg, Sweden; and Department of Endocrinology and Metabolism (H.C.v.B., W.M.W.), Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Sofia Tedelind, Institute of Biomedicine, Department of Medical Chemistry and Cell Biology, Sahlgrenska Academy at Göteborg University, Box 420, 405 30 Göteborg, Sweden. E-mail: sofia.tedelind{at}anatcell.gu.se.

Thyroid side effects are common in patients treated for cardiac arrhythmias with amiodarone (AM). A major disturbance is inhibited thyroidal radioiodine uptake in AM-induced thyrotoxicosis, which makes ¹³¹I therapy ineffective. On the other hand, failure to escape from the Wolff-Chaikoff effect by down-regulation of the sodium/iodide symporter (NIS) is proposed to explain AM-induced hypothyroidism. However, previously no experimental studies on the possible mechanisms have been conducted. We therefore investigated the early effects of AM on thyroidal iodide transport using bicameral chamber cultures of primary pig thyrocytes that reproduce the three tissue compartments (epithelium, lumen, and extrafollicular space) of the gland. AM dose-dependently (1–50 µM) inhibited the TSH-stimulated transepithelial (basal to apical) transport of ¹²⁵I^– by up to 90%. The inhibitory effect was noticed already after 8 h and was further pronounced after 1–4 d, depending on the AM concentration. The intracellularly accumulated ¹²⁵I^– was reduced by perchlorate but not AM, and quantitative real-time RT-PCR revealed no change in the NIS expression in AM-treated cells. Blocking of cAMP degradation with 3-isobutyl-1-methylxanthine or withdrawal of AM reversed AM-induced changes in electrolyte transport but were unable to recover the suppressed ¹²⁵I^– transport. The iodine-free AM analog dronedarone also inhibited ¹²⁵I^– transport to the same extent as AM. The findings indicate that AM blocks thyroidal iodide uptake by reducing the iodide permeability of the apical plasma membrane of the thyroid epithelial cells. The effect is iodine independent and long-lasting and does not involve impaired function of NIS or the TSH receptor/cAMP signaling pathway.