特异性甲状腺激素受体 α(1)和β(1)拮抗剂在大鼠甲状腺激素代谢的中枢和外周调节中的作用。

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.

机构信息

Department of Endocrinology & Metabolism, Laboratory of Endocrinology, University of Amsterdam, Amsterdam, The Netherlands.

出版信息

Thyroid. 2012 Dec;22(12):1275-82. doi: 10.1089/thy.2012.0135.

DOI:10.1089/thy.2012.0135

PMID:22985455

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.

CONCLUSION

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.

摘要

背景

含碘药物胺碘酮（Amio）及其非碘类似物决奈达隆（Dron）是强效抗心律失常药物。先前的体内和体外研究表明，Amio 的主要代谢物去乙基胺碘酮作为甲状腺激素受体（TR）α(1)和β(1)拮抗剂，而 Dron 的主要代谢物 debutyldronedarone 作为选择性 TRα(1)拮抗剂。在本研究中，Amio 和 Dron 被用作工具，以区分中枢和外周甲状腺激素代谢中 TRα(1)或 TRβ(1)调节的基因。

方法

三组雄性大鼠分别接受 Amio、Dron 或载体每日胃内给药 2 周。我们评估了治疗对三碘甲状腺原氨酸（T(3)）和甲状腺素（T(4)）血浆和组织浓度、脱碘酶 1、2 和 3 mRNA 表达和活性以及甲状腺激素转运蛋白单羧酸转运蛋白 8（MCT8）、单羧酸转运蛋白 10（MCT10）和有机阴离子转运蛋白 1C1（OATP1C1）的影响。

结果

与 Dron 治疗和对照组大鼠相比，Amio 治疗降低了血清 T(3)，而血清 T(4)和促甲状腺激素（TSH）升高。在下丘脑-垂体-甲状腺轴的中枢水平，Amio 治疗降低了下丘脑促甲状腺素释放激素（TRH）的表达，同时增加了垂体 TSHβ 和 MCT10 mRNA 的表达。Amio 降低了垂体 D2 活性。相比之下，Dron 治疗仅导致下丘脑 TRH mRNA 表达降低。在用 Amio 治疗后，与 Dron 和对照组大鼠相比，肝脏 T(3)浓度显著降低（50%，p<0.01），但肝脏 T(4)浓度不受影响。此外，肝脏 D1 mRNA 和活性降低，而 D3 活性和 mRNA 增加。各组之间的肝脏 MCT8、MCT10 和 OATP1C1 mRNA 表达相似。