Studies on the nature of iodothyronine binding in familial dysalbuminemic hyperthyroxinemia.
The effects of pH and anionic binding inhibitors were used to test the hypothesis that the increased T4 binding affinity of the variant albumin (Alb-FDH) of familial dysalbuminemic hyperthyroxinemia (FDH) is due to an electrostatic bond with the ionized phenolic hydroxyl of the iodothyronine. As determined by charcoal adsorption from 2% serum in which binding to T4-binding globulin and transthyretin had been inhibited, increased T4 binding by Alb-FDH was pH dependent and proportional to the ionization of the phenolic hydroxyl. Increased T3 binding became apparent above physiological pH, as is consistent with the higher pK of the T3 phenolic hydroxyl. The iodothyroacetic analogs of T4 and T3 developed maximal increases in binding to Alb-FDH at about the same pH as the corresponding iodothyronines. Aspirin, salicylate, warfarin, and chloride, anions that have minimal stereochemical resemblance to the iodothyronines but bind to albumin cationic groups, inhibited T4 binding to FDH sera at concentrations that had little or no effect on binding in normal sera. Increased displacement of T4 from Alb-FDH by salicylate was also evident at therapeutic ratios to a 1:1 dilution of serum in a dialysis system. Aspirin displaced T4 at a lower pH than T3, as is consistent with competition with the ionized iodothyronine phenolic group. These findings suggest that an electrostatic bond between the iodothyronine phenolate and a cationic group on the protein is the basis for the increased affinity and specificity of Alb-FDH for T4.
Divino
C M
CM
Department of Medicine, State University of New York Health Science Center, Brooklyn 11203-2098.
Schussler
G C
GC
D001241:Aspirin / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology; D005260:Female; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006981:Hyperthyroxinemia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012709:Serum Albumin / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*; D014859:Warfarin / Q000494:pharmacology
D002712:Chlorides; D012709:Serum Albumin; D014284:Triiodothyronine; D014859:Warfarin; D013974:Thyroxine; D001241:Aspirin