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Antithyroid Effect of Noncalorigenic Congeners of Salicylate, with Observations on the Influence of Serum Proteins on the Potency of Antithyroid Agents

Thorndike Memorial Laboratory, Second and Fourth (Harvard) Medical Services, Boston City Hospital, and the Department of Medicine, Harvard Medical School Boston, Massachusetts

This investigation was supported in part by Research Grant AM-00267-10 from the National Institute of Arthritis and Metabolic Diseases, NIH, Bethesda, Maryland.

Abstract

Several congeners of salicylate, previously shown to inhibit the binding of thyroxine in serum and to alter its peripheral metabolism in man, have been found to inhibit thyroid hormone synthesis. The most potent were 2,3-dihydroxybenzoic acid, 3,5- dihydroxybenzoic acid, 2,4-dihydroxybenzoic (beta-resorcylic) acid, and 2,6-dihydroxybenzoic (gamma-resorcylic) acid. In vitro, these compounds inhibit the organic binding of thyroidal iodide. In rats, gamma-resorcylic acid also inhibited both the iodination of monoiodotyrosine to form diiodotyrosine and the coupling of iodotyrosines to form iodothyronines. As might be expected from their effects on thyroxine binding, which suggest that they themselves are bound to serum proteins, the antithyroid activity of these compounds was decreased in vitro by the presence of human serum. This observation led to a study of the effects of serum on the in vitro activity of the traditional antithyroid agents. In protein-free media, propylthiouracil was much more potent than equimolar concentrations of thiouracil. In the presence of serum, however, the activity of a standard concentration of propylthiouracil was decreased and that of thiouracil essentially unchanged, with the result that their antithyroid activities were virtually equal. The activity of methimazole was modified only slightly by the presence of human serum. It is suggested that the individual binding properties of the antithyroid agents may modify their activity in such a way as to account both for the discrepancy between their in vitro activity and their activity in man and for their varying potencies among different species. (Endocrinology 76: 584, 1965)

Received July 15, 1964.