Context: Methimazole (MMI) and propylthiouracil (PTU) are widely used as anti-thyroid 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 thyroxine in peripheral tissues. ATDs may also interfere with triiodothyronine (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 growth hormone (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 nuclear corepressors, NCoR, to the TR in the absence of T3. In addition, PTU dissociated nuclear coactivators, such as SRC-1 and GRIP-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.