|Budget Amount *help
¥9,400,000 (Direct Cost: ¥9,400,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2001: ¥6,700,000 (Direct Cost: ¥6,700,000)
We investigated the effects of phenolic and phenol compounds on 3,3',5-[^<125>I]triiodothyronine ([^<125>I]T_3) binding to purified Xenopus laevis transthyretin (xTTR) and to the ligand-binding domain of X. laevis thyroid hormone receptor β (xTR LBD), on T_3-induced metamorphosis in X. laevis tadpoles and on the induction of T_3-dependent reporter gene in a X. laevis cell line. Of the halogenated phenolic and phenol compounds tested, 3,3',5-trichlorobisphenol A and 2,4,6-triiodophenol, respectively, were the most potent competitors of [^<125>I]T_3 binding to both xTTR and xTR LBD. Most of the halogenated compounds had stronger interactions with xTTR than with xTR LBD. Generally, chlorinated derivatives with a greater degree of chlorination were more efficient competitors of T_3 binding to xTTR and xTR LBD. Structures with a halogen in either ortho positions or in both ortho positions, with respect to the hydroxy group, were more efficient competitors. 3,3',5-Trichlorobisphenol A and 2,4,6-triiodophenol acted as T_3 antagonists in the X laevis tadpole metamorphosis assay. Interestingly, o-t-butylphenol and 2-isopropylphenol, for which xTTR and xTR LBD had weak or no significant affinity, showed T_3 antagonist activity in the metamorphosis assay. T_3 antagonist activities of all these chemicals except for o-t-butylphenol were verified by T_3-dependent reporter gene assay. Our results suggest that some phenolic and phenol compounds target the process of T_3 binding to xTTR and xTR and/or an unknown process, and that they interfere with the intracellular T_3 signaling pathway.