Mechanism of inactivation of thyroid peroxidase by thioureylene drugs.
We have investigated the mechanism by which the thioureylene drugs, 1-methyl-2-mercaptoimidazole (MMI) and 6-n-propylthiouracil (PTU), inactivate thyroid peroxidase (TPO). Our results indicate that inactivation of TPO by MMI and PTU involves a reaction between the drugs and the oxidized heme group produced by interaction between TPO and H2O2. This conclusion is supported by the following observations. First, addition of a low concentration of H2O2 to a solution of TPO shifted lambda max of the Soret band from 411 to 420 nm, reflecting the formation of an oxidized form of TPO (TPOox). Addition of MMI or PTU to TPOox produced a Soret spectrum that was significantly different from the spectrum of native TPO or TPOox, whereas addition of MMI or PTU to native TPO produced no significant change in the heme spectrum. Second, studies with radiolabeled MMI and PTU combined with simultaneous assays of enzyme activity (guaiacol assay) showed that firm binding of the drugs to TPO and inactivation of the enzyme occurred on addition of the drugs to TPOox. However, neither binding nor inactivation occurred on addition of the drugs to native TPO. Third, the presence of a low concentration of iodide prevented the shift in the Soret spectrum, the binding of labeled drug, and the loss of enzyme activity associated with the addition of thioureylene drugs to TPO + H2O2. Under these conditions we assume that the enzyme was present as TPO X Iox, a form in which the heme is present in the same reduced state as in native TPO. This would explain the protective action of iodide on the inactivation of TPOox by MMI and PTU.
D013956:Antithyroid Agents / Q000494:pharmacology*; D006139:Guaiacol / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007454:Iodides / Q000494:pharmacology; D007700:Kinetics; D008713:Methimazole / Q000494:pharmacology*; D010544:Peroxidases / Q000037:antagonists & inhibitors*; D011441:Propylthiouracil / Q000494:pharmacology; D013961:Thyroid Gland / Q000201:enzymology*
D013956:Antithyroid Agents; D007454:Iodides; D006418:Heme; D008713:Methimazole; D006139:Guaiacol; D011441:Propylthiouracil; D006861:Hydrogen Peroxide; D010544:Peroxidases