Desethylamiodarone interferes with the binding of co‐activator GRIP‐1 to the β1‐thyroid hormone receptor

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Abstract
Ligand binding to the thyroid hormone nuclear receptor β1 (TRβ1) is inhibited by desethylamiodarone (DEA), the major metabolite of the widely used anti‐arrhythmic drug amiodarone. Gene expression of thyroid hormone (triiodothyronine, T3)‐regulated genes can therefore be affected by amiodarone due to less ligand binding to the receptor. Previous studies have indicated the possibility of still other explanations for the inhibitory effects of amiodarone on T3‐dependent gene expression, probably via interference with receptor/co‐activator and co‐repressor complex. The binding site of DEA is postulated to be on the outside surface of the receptor protein overlapping the regions where co‐activator and co‐repressor bind. Here we show the effect of a drug metabolite on the interaction of TRβ1 with the co‐activator GRIP‐1 (glucocorticoid receptor interacting protein‐1). The T3‐dependent binding of GRIP‐1 to the TRβ1 is disrupted by DEA. A DEA dose experiment showed that the drug metabolite acts like an antagonist under ‘normal’ conditions (at 10−7 M T3 and 5×10−6→10−3 M DEA), but as an agonist under extreme conditions (at 0 and 10−9 M T3 and >10−4 M DEA). To our knowledge, these results show for the first time that a metabolite of a drug which was not devised for this purpose can interfere with nuclear receptor/co‐activator interaction.