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Studies on the Nature of Iodothyronine Binding in Familial Dysalbuminemic Hyperthyroxinemia^*

Department of Medicine, State University of New York Health Science Center Brooklyn, New York 11203-2098

Address all correspondence and requests for reprints to: Dr. Schussler, Box 21, 450 Clarkson Avenue, Brooklyn, New York 11203.

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 dysalbu-minemic 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.

^* This work was supported by Grant 5R01-AM-32436 from the NIH and a grant from the Division of Research Resources, State University of New York Health Science Center at Brooklyn.

Received August 23, 1989.

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