Journal of Clinical Endocrinology & Metabolism, Vol 68, 1141-1147, Copyright © 1989 by Endocrine Society

ARTICLES

Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin

SL Munro, CF Lim, JG Hall, JW Barlow, DJ Craik, DJ Topliss and JR Stockigt
Ewen Downie Metabolic Unit, Alfred Hospital, Melbourne, Victoria, Australia.

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.

This article has been cited by other articles:

				B. McKinnon, H. Li, K. Richard, and R. Mortimer Synthesis of Thyroid Hormone Binding Proteins Transthyretin and Albumin by Human Trophoblast J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6714 - 6720. [Abstract] [Full Text] [PDF]

				M. H. Samuels, K. Pillote, D. Asher, and J. C. Nelson Variable Effects of Nonsteroidal Antiinflammatory Agents on Thyroid Test Results J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5710 - 5716. [Abstract] [Full Text] [PDF]

				H. E. Purkey, M. I. Dorrell, and J. W. Kelly Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma PNAS, May 8, 2001; 98(10): 5566 - 5571. [Abstract] [Full Text] [PDF]

				S. A. Peterson, T. Klabunde, H. A. Lashuel, H. Purkey, J. C. Sacchettini, and J. W. Kelly Inhibiting transthyretin conformational changes that lead to amyloid fibril formation PNAS, October 27, 1998; 95(22): 12956 - 12960. [Abstract] [Full Text] [PDF]

				J. A. Wilce, S. G. Love, S. J. Richardson, P. F. Alewood, and D. J. Craik Synthesis of an Analog of the Thyroid Hormone-binding Protein Transthyretin via Regioselective Chemical Ligation J. Biol. Chem., July 6, 2001; 276(28): 25997 - 26003. [Abstract] [Full Text] [PDF]