Triiodothyroacetic acid has unique potential for therapy of resistance to thyroid hormone

Abstract

3,5,3'-Triiodothyroacetic acid (Triac) has been used in therapy of resistance to thyroid hormone on an empirical basis and appears beneficial in some studies. We observed that the T3 analogs, Triac and 3,5,3'- triiodothyropropionic acid (Triprop), have a higher affinity for the thyroid hormone receptor-β1 (TRβ1) than does T3 (2.7- and 1.8-fold, respectively), whereas the affinities of the three compounds for TRα1 are the same. To evaluate whether T3 analogs would have a differential effect on TRβ1 and TRβ1 mutants and thus be a specific treatment for patients with resistance to thyroid hormone, we examined the induction of the transcriptional activation of wild-type (wt) TRα1, TRβ1, and mutant TRβ1s by T3, Triac, and Triprop. The dose response of transcriptional activation by T3 analogs was measured by transient cotransfections with TRs and a rat malic enzyme- TRE fused to thymidine kinase (TK)-chloramphenicol acetyltransferase (CAT) in COS-1 cells. For TRα1wt, induction of CAT activity by T3 and Triac occurred at the same concentration. For TRβ1wt, Triac and Triptop showed a higher maximal activity than T3 (Tripro ≥ Triac > T3) and reached 50% induction at a lower concentration than T3 (Tripro < Triac