Binding Globulin by Analogues of Hydantoin

Administration of the anticonvulsant 5,5-diphenylhydantoin sodium (DPH, Dilantin) depresses the level of serum protein-bound iodine (PBI) without inducing clinical hypothyroidism or changing other measures of thyroid function, such as 24-hour thyroidal accumulation of I131, thyroidal clearance of I131, serum cholesterol, and basal metabolic rate (1). Since DPH also induces a fall in the serum PBI of hypothyroid and hypopituitary patients maintained on a constant exogenous dose of dessicated thyroid, the action of DPH must be largely extrathyroidal. DPH has also been shown to interfere with the binding of thyroxine (T4) by plasma proteins, as measured by the increased uptake of I131 L-triiodothyronine (T-I131) and 1131 L-thyroxine (T4-I"31) by red cells (1, 2), as well as by the increased dialysis of T4 across a semipermeable membrane after the addition of DPH to serum (2). It appears probable that fall in circulating PBI is due to this inhibition of protein-binding. Electrophoretic studies (2, 3) have indicated that DPH appears to interfere with the binding, specifically, of the alpha globulin carrier of T4, thyroxine-binding globulin (TBG). In vitro addition of DPH causes a displacement of T4 from alpha globulin to prealbumin and albumin. The present studies were undertaken to determine 1) the reversibility and specificity of the interaction between DPH and T4 at the alpha globulin binding site and 2) the structural requirements of the DPH molecule necessary for this phenomenon.