Antagonism of thyroid hormone action by amiodarone in rat pituitary tumor cells.

Abstract

A thyroid hormone antagonist has not been previously described. A number of thyroid hormone analogues have been shown to compete with ["25Iltriiodothyronine (1125I1T3) for bind-ing to the intranuclear thyroid hormone receptor and to have agonist activity proportional to their affinities for the receptors. We report that the benzofuran amiodarone acts as a competitive antagonist to thyroid hormone action as defined by its dose-dependent ability to (a) bind to the thyroid hormone receptor and (b) inhibit T3-induced increases in growth hormone mRNA levels in a cultured rat pituitary cell line, GC cells. Like T3 itself, amiodarone also decreases transport of 112511T3 across GC cell membranes. An analysis of the amiodarone structure suggests that this compound has certain similarities to T3. These findings hold promise for the development of other thyroid hormone antagonists for clinical use and for understanding thyroid hormone action.

A Thyroid Hormone Antagonist That Inhibits Thyroid Hormone Action in Vivo

“…Maximal resorption rate is induced above 30 nM in this assay. 4 As shown in that at this concentration NH-3 may have some partial agonist activity not observed in transient transfection assays.…”

“…To date, the development of potent antagonists has proven problematic. The cardiac arrhythmia drug amiodarone and its primary metabolite, desethylamiodarone, have been proposed to function in part as thyroid hormone receptor antagonists (4). However, these compounds bind to TRs with relatively low affinity and have complex effects on receptor function, showing both agonist and antagonist activity depending on the assay (5).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Patients receiving amiodarone typically have a decrease in T4 to T3 conversion due to an inhibition of D1 and D2 (108)(109)(110). Patients receiving levothyroxine for hypothyroidism often require an increase in their dosage with amiodarone treatment.…”

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

“…At the cellular level, in addition to the inhibition of type I and type II iodothyronine 5 H -deiodinase (11,12), amiodarone can also act as a competitive antagonist of tri-iodothyronine (T 3 ) in cultured rat pituitary cells (13), and induce a hypothyroid-like condition. Similar to what is observed in hypothyroidism, amiodarone decreases the number of catecholamine receptors (14,15), and reduces the effect of T 3 on b-adrenergic receptors (16).…”

“…Amiodarone is also likely to antagonize the effects of thyroid hormone by a competitively binding to thyroid hormone receptor (TR) both in vivo and in vitro (17±19). Furthermore, the drug inhibits the thyroid hormone-mediated increase in growth hormone mRNA levels in cell cultures (13). Hudig et al (20) reported that, in amiodarone-treated animals, the drug-induced hypercholesterolaemia was due to a reduction of low-density lipoprotein (LDL) receptor mRNA levels, thus suggesting that the drug induced a hypothyroid-like condition in the liver.…”