title: Action of specific thyroid hormone receptor α(1) and β(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat.
abstract: BACKGROUND
  The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) α(1) and β(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TRα(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TRα(1) or TRβ(1) regulated genes in central and peripheral thyroid hormone metabolism.
  
  
  METHODS
  Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T(3)) and thyroxine (T(4)) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1).
  
  
  RESULTS
  Amio treatment decreased serum T(3), while serum T(4) and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSHβ and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T(3) concentration decreased substantially compared to Dron and control rats (50%, p<0.01), but liver T(4) concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups.
  
  
  CONCLUSIONS
  Our results suggest an important role for TRα1 in the regulation of hypothalamic TRH mRNA expression, whereas TRβ plays a dominant role in pituitary and liver thyroid hormone metabolism.
authors.affiliation: Department of Endocrinology & Metabolism, Laboratory of Endocrinology, University of Amsterdam, Amsterdam, The Netherlands. h.c.vanbeeren@amc.uva.nl
authors.forename: Hermina C
authors.initials: HC
authors.lastname: van Beeren
authors.forename: Joan
authors.initials: J
authors.lastname: Kwakkel
authors.forename: Mariëtte T
authors.initials: MT
authors.lastname: Ackermans
authors.forename: Wilmar M
authors.initials: WM
authors.lastname: Wiersinga
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
mesh_terms: D000818:Animals; D007031:Hypothalamus / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D010902:Pituitary Gland / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D037021:Thyroid Hormone Receptors alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D037042:Thyroid Hormone Receptors beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D007453:Iodide Peroxidase