TY - JOUR
T1 - Action of Specific Thyroid Hormone Receptor alpha(1) and beta(1) Antagonists in the Central and Peripheral Regulation of Thyroid Hormone Metabolism in the Rat
AU - van Beeren, Hermina C.
AU - Kwakkel, Joan
AU - Ackermans, Mariëtte T.
AU - Wiersinga, Wilmar M.
AU - Fliers, Eric
AU - Boelen, Anita
PY - 2012
Y1 - 2012
N2 - 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) alpha(1) and beta(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TR alpha(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TR alpha(1) or TR beta(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 TSH beta 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 T3 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. Conclusion: Our results suggest an important role for TR alpha(1) in the regulation of hypothalamic TRH mRNA expression, whereas TR beta plays a dominant role in pituitary and liver thyroid hormone metabolism
AB - 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) alpha(1) and beta(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TR alpha(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TR alpha(1) or TR beta(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 TSH beta 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 T3 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. Conclusion: Our results suggest an important role for TR alpha(1) in the regulation of hypothalamic TRH mRNA expression, whereas TR beta plays a dominant role in pituitary and liver thyroid hormone metabolism
U2 - https://doi.org/10.1089/thy.2012.0135
DO - https://doi.org/10.1089/thy.2012.0135
M3 - Article
C2 - 22985455
SN - 1050-7256
VL - 22
SP - 1275
EP - 1282
JO - Thyroid
JF - Thyroid
IS - 12
ER -