Ligand binding to the thyroid hormone nuclear receptor beta1 (TRbeta(1)) is inhibited by desethylamiodarone (DEA), the major metabolite of the widely used anti-arrhythmic drug amiodarone. Gene expression of thyroid hormone (triiodothyronine, T(3))-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 T(3)-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 TRbeta(1) with the co-activator GRIP-1 (glucocorticoid receptor interacting protein-1). The T(3)-dependent binding of GRIP-1 to the TRbeta(1) is disrupted by DEA. A DEA dose experiment showed that the drug metabolite acts like an antagonist under 'normal' conditions (at 10(-7) M T(3) and 5x10(-6)-->10(-3) M DEA), but as an agonist under extreme conditions (at 0 and 10(-9) M T(3) 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.