A thyroid hormone antagonist that inhibits thyroid hormone action in vivo.
We have characterized the newly developed thyroid hormone antagonist NH-3 in both cell culture and in vivo model systems. NH-3 binds Xenopus laevis thyroid hormone receptors directly in vitro and induces a conformation distinct from agonist-bound receptors. Transcriptional activation of a thyroid hormone response element-containing reporter gene is strongly inhibited by NH-3 in a dose-dependent manner. In addition, NH-3 prevents X. laevis thyroid hormone receptors from binding to the p160 family of co-activators GRIP-1 and SRC-1 in a two-hybrid assay. To assess the potency of the compound in vivo, we used induced and spontaneous X. laevis tadpole metamorphosis, a thyroid hormone-dependent developmental process. NH-3 inhibits thyroid hormone-induced morphological changes in a dose-dependent manner and inhibits the up-regulation of endogenous thyroid hormone-responsive genes. Spontaneous metamorphosis is efficiently and reversibly arrested by NH-3 with at least the same effectiveness as the thyroid hormone synthesis inhibitor methimazole. Therefore, NH-3 is the first thyroid hormone antagonist to demonstrate potent inhibition of thyroid hormone action in both cell culture- and whole animal-based assays.
Lim
Wayland
W
Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616-8519, USA.
Nguyen
Ngoc-Ha
NH
Yang
Ha Yung
HY
Scanlan
Thomas S
TS
Furlow
J David
JD
D000085:Acetates / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D013956:Antithyroid Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D006367:HeLa Cells; D006801:Humans; D008675:Metamorphosis, Biological / Q000187:drug effects / Q000502:physiology; D010642:Phenoxyacetates; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013963:Thyroid Hormones / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014982:Xenopus laevis
C461658:(4-(4-hydroxy-3-isopropyl-5-(4-nitrophenylethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid; D000085:Acetates; D013956:Antithyroid Agents; D017931:DNA Primers; D010642:Phenoxyacetates; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones