title: Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription.
abstract: BACKGROUND
  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 T(4) in peripheral tissues. ATDs may also interfere with T(3) binding to nuclear thyroid hormone receptors (TRs). However, the effect of ATDs on the transcriptional activities of T(3) 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 T(3) 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 T(3) 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 T(3). 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 T(3). Finally, MMI decreased the GH release that was stimulated by T(3).
  
  
  CONCLUSIONS
  ATDs inhibit T(3) action by recruitment of transcriptional corepressors and/or dissociation of coactivators. This is the first report to show that ATDs can modulate T(3) action at the transcriptional level.
authors.affiliation: Division of Endocrinology and Metabolism, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Moriyama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tagami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Usui
authors.forename: Mitsuhide
authors.initials: M
authors.lastname: Naruse
authors.forename: Takuo
authors.initials: T
authors.lastname: Nambu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hataya
authors.forename: Naotetsu
authors.initials: N
authors.lastname: Kanamoto
authors.forename: Yu-Shu
authors.initials: YS
authors.lastname: Li
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D013956:Antithyroid Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008713:Methimazole / Q000494:pharmacology; D008954:Models, Biological; D011441:Propylthiouracil / Q000494:pharmacology; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000378:metabolism; D052683:Somatotrophs / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D013956:Antithyroid Agents; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D015534:Trans-Activators; D008713:Methimazole; D011441:Propylthiouracil; D013006:Growth Hormone