Preferential inhibition of thyroxine and 3,5,3'-triiodothyronine formation by propylthiouracil and methylmercaptoimidazole in thyroid peroxidase-catalyzed iodination of thyroglobulin.
The present study was undertaken to determine whether the thioureylene antithyroid drugs propylthiouracil [6-propyl-2-thiouracil (PTU)] and methylmercaptoimidazole [1-methyl-2-mercaptoimidazole (MMI)] have a specific inhibitory effect on the thyroid peroxidase (TPO)-catalyzed conversion of diiodotyrosine to T4 (coupling reaction) independent of their well known inhibitory effect on peroxidase-catalyzed iodination. We have employed model incubation systems containing highly purified TPO to examine this question. Most experiments were performed with a model iodination system containing TPO, low iodine thyroglobulin, [131]iodide, and glucose-glucose oxidase. Both PTU and MMI are effective inhibitors of iodination of this system at physiological concentrations, and the system is well suited for studying the simultaneous action of these drugs on iodination and coupling. The addition of graded doses of the drugs to the iodination system demonstrated a relatively greater inhibitory effect on iodothyronine than on iodotyrosine formation. However, this observation in itself does not establish a specific inhibitory effect on coupling, since the formation of T4 involves a reaction between two molecules of 3,5-diiodotyrosine (DIT). The rate of this reaction, therefore, is second order with respect to DIT concentration, and the inhibition of DIT formation by thioureylene drugs would be expected to result in a disproportionately greater reduction in T4 formation even id there were no selective inhibitory effect of the drugs on the coupling reaction. Under certain conditions of incubation, however, it was possible to demonstrate a significant inhibitory effect on T4 and T3 formation without any decrease (in fact, a slight increase) in diiodotyrosine formation. These observations indicate that, at least under some conditions, PTU and MMI can exert a specific inhibitory effect on the coupling reaction. In the case of PTU, a specific inhibitory effect on coupling was also demonstrated with an incubation system in which TPO-catalyzed coupling was measured in the absence of iodination.
D000818:Animals; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008713:Methimazole / Q000494:pharmacology*; D010544:Peroxidases / Q000037:antagonists & inhibitors*; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D013954:Thyroglobulin / Q000378:metabolism*; D013961:Thyroid Gland / Q000201:enzymology; D013974:Thyroxine / Q000096:biosynthesis*; D014284:Triiodothyronine / Q000096:biosynthesis*
D014284:Triiodothyronine; D008713:Methimazole; D011441:Propylthiouracil; D013954:Thyroglobulin; D010544:Peroxidases; D007453:Iodide Peroxidase; D013974:Thyroxine