Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism

Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is i ts high iodine content, Thyroid dysfunction is a limiting side-effect of th e drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxic osis (AIT) are reported. To examine the hypothesis that altered bioavailabi lity of iodine is a contributing event in the pathogenesis of AIH, Re compa red the effects of;AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (tra nsfected with the human TSH receptor) were exposed to AMD or NaI in the pre sence of TSH, acid cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the poss ible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations o f iodide than those seen in the NaI-treated cells, The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially ove rcome by forskolin but not by cholera toxin indicating an effect on TSH rec eptor interactions with the other signal transduction elements such as G pr oteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyro idism in some patients taking AMD. The combined effects of the constant rel ease of iodide together with the drug toxicity may be the mechanism for the observed effects.