The Irreversible Inactivation of Thyroid Peroxidase by Methylmercaptoimidazole, Thiouracil, and Propylthiouracil in Vitro and Its Relationship to in Vivo Findings*

Abstract

A reinvestigation of the mechanism of action of methylmercaptoimidazole, propylthiouracil, and thiouracil on thyroid peroxidase (TPO) was undertaken. A preliminary incubation of TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or thiouracil was carried out in the absence of oxidizable substrates (i.e. I- or guaiacol). This incubation resulted in irreversible inactivation of TPO. The extent of inactivation could be determined after removal of the drug by gel filtration or by dilution into the assay mixture. Preincubation, as above, in the presence of iodide or thiocyanate prevented the irreversible inactivation of TPO. Rats receiving doses of these drugs which completely inhibited protein-bound iodine formation showed normal levels of TPO in their thyroid glands 30 min after drug administration. These findings suggest that the initial in vivo action of these drugs is to block iodination by trapping oxidized iodide, not by acting as "general inhibitors" of the TPO.

Effect of thione—thiol tautomerism on the inhibition of lactoperoxidase by anti-thyroid drugs and their analogues

“…Taurog and Dorris, on the other hand, suggested that the inhibition of iodination by compounds such as PTU involves a competition reaction between the drugs and tyrosine residues of thyroglobulin (Tg) for oxidized iodine. 14,16 In the present study, we have carried out the enzyme inhibition experiments with lactoperoxidase (LPO, figure 6) since it is readily available in purified form. 17 Furthermore, LPO has been shown to behave similarly to TPO with respect to iodination of thyroglobulin, the natural substrate, and other iodide acceptors.…”

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].…”

Methimazole and Propylthiouracil Increase Cellular Thyroid Peroxidase Activity and Thyroid Peroxidase mRNA in Cultured Porcine Thyroid Follicles

“…It is known that the 2 drugs inhibit thyroid peroxidase (TPO)-catalyzed thyroid hormone formation (4); thus, the 2 drugs are mistakenly labeled as a TPO inhibitors by many clinicians. The antithyroid mechanisms of the 2 drugs have been described in the iodination system of cellfree experiments (5)(6)(7) and in vivo experiments in rats (7)(8)(9). These studies revealed reversible and irreversible inhibition of TPO-mediated reaction, as summarized by Taurog (10).…”