Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin.
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.
Munro
S L
SL
Ewen Downie Metabolic Unit, Alfred Hospital, Melbourne, Victoria, Australia.
Lim
C F
CF
Hall
J G
JG
Barlow
J W
JW
Craik
D J
DJ
Topliss
D J
DJ
Stockigt
J R
JR
D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D001692:Biological Transport; D004061:Diflunisal / Q000494:pharmacology*; D005439:Flufenamic Acid / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008528:Mefenamic Acid / Q000494:pharmacology*; D011228:Prealbumin / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism*; D013975:Thyroxine-Binding Proteins / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D011228:Prealbumin; D012459:Salicylates; D013975:Thyroxine-Binding Proteins; D014284:Triiodothyronine; D008528:Mefenamic Acid; D005439:Flufenamic Acid; D004061:Diflunisal; D013974:Thyroxine