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Antithyroid Drugs Inhibit Thyroid Hormone Receptor-Mediated Transcription

Department of Medicine and Clinical Science (K.M., T.N., Y.H., N.K., Y.L., A.Y., H.A., K.N.), Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; and Division of Endocrinology and Metabolism (K.M., T.T., T.U., M.N.), Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan

Address all correspondence and requests for reprints to: Tetsuya Tagami, M.D., Ph.D., Division of Endocrinology and Metabolism, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan. E-mail: ttagami{at}kyotolan.hosp.go.jp.

Context: Methimazole (MMI) and propylthiouracil (PTU) are widely used as antithyroid drugs (ATDs) for the treatment of Graves’ disease. Both MMI and PTU reduce thyroid hormone levels by several mechanisms, including inhibition of thyroid hormone synthesis and secretion. In addition, PTU decreases 5'-deiodination of T₄ in peripheral tissues. ATDs may also interfere with T₃ binding to nuclear thyroid hormone receptors (TRs). However, the effect of ATDs on the transcriptional activities of T₃ mediated by TRs has not been studied.

Objective: The present study was undertaken to determine whether ATDs have an effect on the gene transcription regulated by T₃ and TRs in vitro.

Methods: Transient gene expression experiments and GH secretion assays were performed. To elucidate possible mechanisms of the antagonistic action of ATDs, the interaction between TR and nuclear cofactors was examined.

Results: In the transient gene expression experiments, both MMI and PTU significantly suppressed transcriptional activities mediated by the TR and T₃ in a dose-dependent manner. In mammalian two-hybrid assays, both drugs recruited one of the nuclear corepressors, nuclear receptor corepressor, to the TR in the absence of T₃. In addition, PTU dissociated nuclear coactivators, such as steroid receptor coactivator-1 and glucocorticoid receptor interacting protein-1, from the TR in the presence of T₃. Finally, MMI decreased the GH release that was stimulated by T₃.

Conclusions: ATDs inhibit T₃ action by recruitment of transcriptional corepressors and/or dissociation of coactivators. This is the first report to show that ATDs can modulate T₃ action at the transcriptional level.

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