title: Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone alpha 1-receptor protein.
abstract: Desethylamiodarone (DEA), the major metabolite of the potent antiarrythmic drug amiodarone, is a non-competitive inhibitor of the binding of thyroid hormone (T3) to the beta 1-thyroid hormone receptor (T3R). In the present study, we investigated whether DEA acts in a similar way with respect to the alpha 1-T3R. The chicken alpha 1-T3R, expressed in an E. coli system, was incubated in the presence or absence of DEA with [125I]T3 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 T3 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 Ka 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 [125I]T3 binding, which was independent of the duration of pre-incubation. In conclusion, in contrast to the beta 1-T3R, where DEA acts as a non-competitive inhibitor, we now report as a new finding the competitive action of DEA to the alpha 1-T3R.
authors.affiliation: Department of Endocrinology, University of Amsterdam, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: van Beeren
authors.forename: O
authors.initials: O
authors.lastname: Bakker
authors.forename: W M
authors.initials: WM
authors.lastname: Wiersinga
mesh_terms: D000595:Amino Acid Sequence; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002645:Chickens; D004926:Escherichia coli / Q000235:genetics; D007457:Iodine Radioisotopes; D007700:Kinetics; D008969:Molecular Sequence Data; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014284:Triiodothyronine / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007457:Iodine Radioisotopes; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D014284:Triiodothyronine; C036116:desethylamiodarone; D000638:Amiodarone