The Mechanism of Action of the Thioureylene Antithyroid Drugs

Abstract

A model incubation system containing purified thyroid peroxidase (TPO) was used to study the mechanism of action of the thioureylene anti-thyroid drugs--propylthiouracil (PTU), methylmercapto imidazole (MMI) and carbimazole. Two general types of experiments were performed: a) measurement of the inhibitory effects of the drugs on TPO-catalyzed iodination and on TPO-catalyzed oxidation of guaiacol, and b) studies of the metabolism of PTU and MMI by the TPO model system. The major observations can be summarized as follows: 1) The thioureylene drugs are potent inhibitors of TPO-catalyzed iodination of protein and tyrosine. Their potency increases greatly as the concentration of I- decreases. 2) The thioureylene drugs are also potent inhibitors of TPO-catalyzed oxidation of guaiacol, a reaction that does not involve iodide. 3) MMI and PTU are readily oxidized in the model incubation system when iodide is present but not in the absence of iodide. The rate of oxidation increased as the iodide concentration was increased from 10 to 100 muM. 4) Oxidation of PTU and MMI by the model incubation system is inhibited by relatively slight increases in the concentration of PTU and MMI. These drugs are capable of inhibiting their own and each other's metabolism. 5) Inhibition of iodination is competitively antagonized by iodide at low drug concentrations, but not at higher drug concentrations. 6) Inhibition of iodination by MMI and PTU may be either reversible (low ratio of drug to iodide), or irreversible (higher ratio of drug to iodide). In reversible inhibition the iodination is inhibited for a period which may be as brief as 2 min or as long as 20 min, but thereafter, iodination begins, and there is escape from inhibition. During the lag-period there is extensive metabolism of the drug. In the case of irreversible inhibition of iodination is inhibited completely or almost completely for 60 min, and drug oxidation during this period is relatively low. 7) Irreversible inhibition may be transformed into reversible inhibition by increasing the concentration of TPO or the concentration of iodide. However, increasing the concentration of H2O2 or of tyrosine does not overcome irreversible inhibition. On the basis of these findings and of current views concerning the mechanism of enzymatic iodination, a scheme is proposed for the mechanism of inhibition by thioureylene drugs of TPO-catalyzed iodination of protein and tyrosine.

Experimental targeted radioiodide therapy following transfection of the sodium iodide symporter gene: Effect on clonogenicity in both two-and three-dimensional models

“…11 However, the observed rates of I À uptake and efflux are similar to those observed in other NIStransfected cell lines, 5,8,9 again implying that I À uptake is solely dependent on NIS expression.…”

Thyroid Hyperactivity Induced by Methimazole, Spironolactone and Phenobarbital in Marmosets (Callithrix jacchus): Histopathology, Plasma Thyroid Hormone Levels and Hepatic T4 Metabolism.

“…MMI, an anti-thyroid drug, impairs the synthesis of thyroid hormones by inhibiting the peroxidase [25]. In rats, a 4-fold increase in thyroid weight has been induced after one-month of MMI treatment (90 ppm in diet, approx.…”

An Analysis for Aggravation of Thyroid Function After Discontinuing Potassium Iodine in Graves’ Patients Treated With Methimazole and Potassium Iodine

“…Therefore, KI has been generally prescribed in limited situations such as preparation for thyroidectomy, treatment after radioactive iodine therapy for GD and correction of thyroid function of patients suffering from adverse effects of ATDs [6,7,13,14]. In addition, iodine administration in combination with ATDs has been reported to reduce the efficacy of ATDs in vitro [15][16][17]. There are also some reports that the combination of ATDs with iodine was not effective and KI monotherapy of GD impaired the efficacy of subsequent ATDs therapy [18,19].…”