Antithyroid Properties of 3-Hydroxy-4(lH)-Pyridone: Antiperoxidase Activity and Effect on Thyroid Function*

Abstract

Confirmation of the antithyroid properties of the recently identified goitrogen 3-hydroxy-4(lH)-pyridone (DHP) was obtained by studying its effects on thyroid hormone levels in mice fed a restricted iodine diet containing 1% (wt/wt) DHP. Besides producing hyperplastic goiters, the compound depressed serum T₄ concentration, caused a marked elevation in serum T₃ uptake and TSH, and caused a slight increase in T₃ concentration relative to controls. The effects of DHP on thyroid function were consistent with the histological changes and similar to those reported with other active antithyroid compounds. However, DHP is chemically distinct from any hitherto recognized goitrogen. Its mode of action was further investigated by testing for antiperoxidase activity, because many known goitrogens are general peroxidase inhibitors. A pig thyroid peroxidase preparation and a commercial lactoperoxidase were used. Like the known antithyroid agents resorcinol and 6-methyl-2-thiouracil, DHP was a potent inhibitor of four thyroid peroxidase- and lactoperoxidase-catalyzed reactions, namely 1) oxidation of iodide to iodine, 2) iodination of thyroglobulin, 3) iodination of bovine serum albumin, and 4) oxidation of guaiacol. Based on the concentrations necessary for 50% inhibition, the activity of DHP was less than that of resorcinol and about the same as that of 6-methyl-2-thiouracil. The two major conjugated forms found in mammals, DHP-3-O-glucuronide and DHP-3-O-sulphate, were only weak peroxidase inhibitors. The relevance of these findings to the occurrence of goiter in ruminants grazing on the tropical legume Leucaena leucocephala is discussed, and it is concluded that DHP is the proximate goitrogen, formed by ruminal metabolism of the nonprotein plant amino acid mimosine.