In vitro and in vivo analysis of the thyroid disrupting activities of phenolic and phenol compounds in Xenopus laevis.
In vitro and in vivo analysis of the thyroid disrupting activities of phenolic and phenol compounds in Xenopus laevis.
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DOI：
10.1093/toxsci/kfi049
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发表时间：
2005-03
期刊：
影响因子：
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通讯作者：
Yumiko Kudo;K. Yamauchi
中科院分区：
文献类型：
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作者：
Yumiko Kudo;K. Yamauchi
我们研究了酚类和苯酚化合物对 3,3',5-L-125I-三碘甲状腺原氨酸 (125I-T3) 与纯化非洲爪蟾转甲状腺素蛋白 (xTTR) 和非洲爪蟾甲状腺激素受体 β (xTR LBD) 配体结合结构域的影响、对非洲爪蟾蝌蚪 T3 诱导的变态以及对 T3 依赖性报告基因诱导的影响。 X. laevis 细胞系。在测试的卤代酚类和苯酚化合物中，3,3',5-三氯双酚 A 和 2,4,6-三碘苯酚分别是 125I-T3 与 xTTR 和 xTR LBD 结合的最有力竞争者。大多数卤代化合物与 xTTR 的相互作用强于与 xTR LBD 的相互作用。一般来说，氯化程度较高的氯化衍生物是 T3 与 xTTR 和 xTR LBD 结合的更有效的竞争者。相对于羟基，在邻位或两个邻位都有卤素的结构是更有效的竞争者。 3,3',5-三氯双酚 A 和 2,4,6-三碘苯酚在 X. laevis 蝌蚪变态试验中充当 T3 拮抗剂。有趣的是，xTTR 和 xTR LBD 对邻叔丁基苯酚和 2-异丙基苯酚具有弱亲和力或无显着亲和力，但它们在变态试验中显示出 T3 拮抗剂活性。除邻叔丁基苯酚外，所有这些化学物质的 T3 拮抗剂活性均通过 T3 依赖性报告基因测定进行了验证。我们的结果表明，一些酚类和酚类化合物靶向 T3 与 xTTR 和 xTR 结合的过程和/或未知过程，并且它们干扰细胞内 T3 信号传导途径。
We investigated the effects of phenolic and phenol compounds on 3,3',5-L-125I-triiodothyronine (125I-T3) binding to purified Xenopus laevis transthyretin (xTTR) and to the ligand-binding domain of X. laevis thyroid hormone receptor beta (xTR LBD), on T3-induced metamorphosis in X. laevis tadpoles and on the induction of T3-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 125I-T3 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 T3 binding to xTTR and xTR LBD. Structures with a halogen in either ortho position 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 T3 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 T3 antagonist activity in the metamorphosis assay. T3 antagonist activities of all these chemicals except for o-t-butylphenol were verified by T3-dependent reporter gene assay. Our results suggest that some phenolic and phenol compounds target the process of T3 binding to xTTR and xTR and/or an unknown process, and that they interfere with the intracellular T3 signaling pathway.