Munro S L, Lim C F, Hall J G, Barlow J W, Craik D J, Topliss D J, Stockigt J R
Ewen Downie Metabolic Unit, Alfred Hospital, Melbourne, Victoria, Australia.
J Clin Endocrinol Metab. 1989 Jun;68(6):1141-7. doi: 10.1210/jcem-68-6-1141.
We examined the effect of 26 drugs on T4 binding to transthyretin (TTR; prealbumin) and T4-binding globulin (TBG) by determining their ability to inhibit [125I]T4 binding to TTR isolated from normal human plasma and to serum diluted 1:10,000, respectively. The hierarchies for drug inhibition of T4 binding differed greatly for these two proteins. Relative to T4, the drugs were much more potent inhibitors of [125I]T4 binding to TTR than to TBG. Compounds of the anthranilic acid class, such as flufenamic, meclofenamic, and mefenamic acids, interacted particularly strongly with TTR. Flufenamic acid was more potent than T4 itself in inhibiting [125I]T4 binding [175 +/- 17% (+/- SD); cf. T4; n = 3; P less than 0.001], while mefenamic acid, diflunisal, and meclofenamic acid were 20-26% as potent as T4 in their interaction with TTR. The reactivity of diclofenac, fenclofenac, indomethacin, sulindac, and the diuretic ethacrynic acid was 0.8-2.1% relative to that of T4. In contrast, furosemide, the drug most highly reactive with TBG, was only 0.11 +/- 0.03% (n = 7) as potent as T4, followed by meclofenamic acid greater than mefenamic acid greater than fenclofenac greater than flufenamic acid greater than diflunisal greater than milrinone. Aspirin and sodium salicylate were, respectively, 0.05% and 0.20% as active as unlabeled T4 as inhibitors of [125I]T4 binding to TTR, but these compounds had only 3-4 x 10(-6)% of the activity of T4 for TBG binding. Diphenylhydantoin had no detectable effect on T4 binding to TTR and was 2.9 x 10(-4)% as reactive as T4 with TBG. Amiodarone did not interact with either binding site. Drug interactions with TTR may be important when this protein becomes a major circulating T4-binding protein, as in patients with complete or partial TBG deficiency, or when serum T4 is markedly elevated. Such interactions may also be important where TTR is the dominant tissue T4-binding protein, as in the choroid plexus. In addition, the drug competitors described here may be useful as probes to further define the structural basis for specific ligand interactions with different classes of T4-binding sites.
我们通过测定26种药物抑制[125I]T4与从正常人血浆中分离出的转甲状腺素蛋白（TTR；前白蛋白）以及与稀释1:10000的血清中T4结合球蛋白（TBG）结合的能力，研究了这些药物对T4与TTR和TBG结合的影响。这两种蛋白质的药物抑制T4结合的层次结构差异很大。相对于T4，这些药物对[125I]T4与TTR结合的抑制作用比对TBG结合的抑制作用要强得多。邻氨基苯甲酸类化合物，如氟芬那酸、甲氯芬那酸和甲芬那酸，与TTR的相互作用尤为强烈。氟芬那酸在抑制[125I]T4结合方面比T4本身更有效[175±17%（±标准差）；与T4相比；n = 3；P<0.001]，而甲芬那酸、双氯芬酸和甲氯芬那酸与TTR相互作用的效力为T4的20 - 26%。双氯芬酸、芬氯酸、吲哚美辛、舒林酸和利尿药依他尼酸的反应性相对于T4为0.8 - 2.1%。相比之下，与TBG反应性最高的药物呋塞米，其效力仅为T4的0.11±0.03%（n = 7），其次是甲氯芬那酸>甲芬那酸>芬氯酸>氟芬那酸>双氯芬酸>米力农。阿司匹林和水杨酸钠作为[125I]T4与TTR结合的抑制剂，其活性分别为未标记T4的0.05%和0.20%，但这些化合物对TBG结合的活性仅为T4的3 - 4×10(-6)%。苯妥英对T4与TTR的结合没有可检测到的影响，与TBG反应时其活性为T4的2.9×10(-4)%。胺碘酮与任何一个结合位点均无相互作用。当这种蛋白质成为主要的循环T4结合蛋白时，如在完全或部分TBG缺乏的患者中，或者当血清T4显著升高时，药物与TTR的相互作用可能很重要。在脉络丛中，TTR是主要的组织T4结合蛋白，这种相互作用也可能很重要。此外，本文所述的药物竞争者可能作为探针，用于进一步确定与不同类型T4结合位点特异性配体相互作用的结构基础。
