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

Abstract

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 its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared 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 (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible 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 of 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 overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects.

Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test

“…Its chemical structure resembles that of t4 and the compound alters thyroid hormone levels in vivo (de Sandro et al, 1991), likely due to its high iodide content (Pitsiavas, 1999). In zebrafish, amiodarone was reported to lead to a significant reduction in T4 immunoreactivity at 1 µM (Raldúa and Babin, 2009).…”

More than adequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis: a cross-sectional study based on two Chinese communities with different iodine intake levels

“…The acute Wolff-Chaikoff effect (26,27) suggested that iodine-induced hypothyroidism, especially occurring in patients on amiodarone therapy, is caused by failure of the thyroid gland to escape from acute inhibition (28,29). However, the exact mechanism by which chronic high iodine intake induces hypothyroidism remains unclear.…”

Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

“…Ha et al (2005) reported that mono-N-desethylamiodarone (MDEA) was the major metabolite of amiodarone in human plasma and that further metabolism of MDEA leads to the formation of 3Ј-hydroxyl MDEA, di-N-desethylamiodarone (DDEA), and deaminated amiodarone (DAA). Moreover, amiodarone and its metabolites could release iodine in vivo (Broekhuysen et al, 1969), which may cause amiodarone-induced thyroid dysfunction during therapy (Martino et al, 1984(Martino et al, , 1988Pitsiavas et al, 1999). However, no deiodinated metabolites have ever been detected in humans.…”