DESETHYLAMIODARONE IS A COMPETITIVE INHIBITOR OF THE BINDING OF THYROID-HORMONE TO THE THYROID-HORMONE ALPHA-1-RECEPTOR PROTEIN

Desethylamiodarone (DEA), the major metabolite of the potent antiarrythmic drug amiodarone, is a non-competitive inhibitor of the binding of thyroid hormone (T-3) to the beta 1-thyroid hormone receptor (T(3)R). In the present study, we investigated whether DEA acts in a similar way with respect to the alpha 1-T(3)R. The chicken alpha 1-T(3)R, expressed in an E. coli system, was incubated in the presence or absence of DEA with [I-125]T-3 in buffer containing 0.05% Triton X-100, 0.05% BSA and 1% ethanol (v/v) in order to solubilise DEA. DEA, but not amiodarone, inhibited T-3 binding in a dose-dependent manner; the IC50 value was 3.5 x 10(-5) M. Scatchard analyses in the presence of DEA demonstrated a dose-dependent decrease in K-a values, but no change in MBC. Lineweaver-Burk plots clearly indicated competitive inhibition by DEA. Pre-incubation of the alpha 1-receptor with DEA decreased maximal [I-125]T-3 binding, which was independent of the duration of pre-incubation. In conclusion, in contrast to the beta 1-T(3)R, where DEA acts as a non-competitive inhibitor, we now report as a new finding the competitive action of DEA to the alpha 1-T(3)R.