Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription

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 byT3 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 twohybrid 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.