van den Berg K J
TNO Medical Biological Laboratory, Rijswijk, The Netherlands.
Chem Biol Interact. 1990;76(1):63-75. doi: 10.1016/0009-2797(90)90034-k.
Previous results (Brouwer and van den Berg, Toxicol. Appl. Pharmacol., 85 (1986) 301) indicated preferential binding of a hydroxylated metabolite of tetrachlorobiphenyl to transthyretin (TTR) a carrier of thyroxine (T4). In the present study it was investigated whether the T4 binding site of TTR could be occupied specifically by hydroxylated chlorinated aromatic compounds using chlorinated phenol congeners as model compounds in a competition assay with [125I]T4. Chlorinated aromatics such as 2,3-dichlorobenzene and 3,4,3',4'-tetrachlorobiphenyl, and phenols such as 4-hydroxybiphenyl and phenol were inefficient competitors. All chlorinated phenols tested were competitors for the T4 binding site of TTR. The ranking in competition was pentachlorophenol (PCP) greater than trichlorophenols greater than dichlorophenols greater than monochlorophenols. Structures with chlorine in both ortho positions to the hydroxyl group were more efficient competitors. The relative affinity of binding of pentachlorophenol (PCP) to TTR was about twice that of T4. Scatchard analysis showed that PCP mainly decreased the affinity constant K11 while the binding capacity R1 was not altered, indicating a competitive type of inhibition. PCP was also able to compete with T4 sites on albumin with a relative affinity of 0.25. T4 binding to thyroid binding globulin (TBG) was much less affected by interference of PCP (relative affinity 0.001). The results indicate a specific interaction of chlorophenols with the T4 binding site of TTR.
先前的研究结果（Brouwer和van den Berg，《毒理学与应用药理学》，85卷（1986年），第301页）表明，四氯联苯的一种羟基化代谢物优先与甲状腺素（T4）的载体转甲状腺素蛋白（TTR）结合。在本研究中，使用氯化酚同系物作为模型化合物，通过与[125I]T4的竞争试验，研究了TTR的T4结合位点是否能被羟基化氯代芳香化合物特异性占据。诸如2,3 - 二氯苯和3,4,3',4'-四氯联苯等氯代芳烃，以及诸如4 - 羟基联苯和苯酚等酚类，都是低效的竞争者。所有测试的氯化酚都是TTR的T4结合位点的竞争者。竞争顺序为五氯酚（PCP）大于三氯酚大于二氯酚大于一氯酚。在羟基的两个邻位都有氯的结构是更有效的竞争者。五氯酚（PCP）与TTR的结合相对亲和力约为T4的两倍。Scatchard分析表明，PCP主要降低亲和力常数K11，而结合容量R1未改变，表明是竞争性抑制类型。PCP还能够以0.25的相对亲和力与白蛋白上的T4位点竞争。PCP的干扰对T4与甲状腺结合球蛋白（TBG）的结合影响要小得多（相对亲和力为0.001）。结果表明氯化酚与TTR的T4结合位点存在特异性相互作用。
