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

GEORGE S. CHRISTIE, CHEW P. LEE and MERVYN P. HEGARTY

Department of Pathology, University of Melbourne (G.S.C., C.P.L.) Parkville, Victoria 3052
Division of Tropical Crops and Pastures, C.S.I.R.O. (M.P.H.), St. Lucia Queensland 4067, Australia

Address all correspondence and requests for reprints to: Dr. G. S. Christie, Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.

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.

Footnotes

^* The part of the work carried out in the Department of Pathology, University of Melbourne, was supported by a grant from the Sir A. E. Rowden White Bequest.

Present address: Department of Medicine, University of Tasmania, Hobart, Australia.

Received December 11, 1978.