Taurog A
Endocrinology. 1976 Apr;98(4):1031-46. doi: 10.1210/endo-98-4-1031.
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.
使用包含纯化甲状腺过氧化物酶（TPO）的模型孵育系统来研究硫脲类抗甲状腺药物——丙硫氧嘧啶（PTU）、甲巯咪唑（MMI）和卡比马唑的作用机制。进行了两种一般类型的实验：a）测量药物对TPO催化的碘化作用以及对TPO催化的愈创木酚氧化作用的抑制效果，b）通过TPO模型系统研究PTU和MMI的代谢。主要观察结果可总结如下：1）硫脲类药物是TPO催化的蛋白质和酪氨酸碘化作用的强效抑制剂。随着碘离子浓度降低，它们的效力显著增强。2）硫脲类药物也是TPO催化的愈创木酚氧化作用的强效抑制剂，该反应不涉及碘离子。3）当存在碘离子时，MMI和PTU在模型孵育系统中易于被氧化，但在不存在碘离子时则不然。随着碘离子浓度从10微摩尔增加到100微摩尔，氧化速率增加。4）模型孵育系统对PTU和MMI的氧化作用受到PTU和MMI浓度相对轻微增加的抑制。这些药物能够抑制自身及彼此的代谢。5）在低药物浓度下，碘化作用的抑制被碘离子竞争性拮抗，但在高药物浓度下则不然。6）MMI和PTU对碘化作用的抑制可能是可逆的（药物与碘离子比例低），也可能是不可逆的（药物与碘离子比例高）。在可逆抑制中，碘化作用被抑制一段时间，可能短至2分钟或长达20分钟，但此后，碘化作用开始，且抑制作用解除。在延迟期内，药物有广泛的代谢。在不可逆抑制碘化作用的情况下，碘化作用被完全或几乎完全抑制60分钟，在此期间药物氧化相对较低。7）通过增加TPO浓度或碘离子浓度，不可逆抑制可转变为可逆抑制。然而，增加过氧化氢或酪氨酸的浓度并不能克服不可逆抑制。基于这些发现以及当前关于酶促碘化作用机制的观点，提出了硫脲类药物抑制TPO催化的蛋白质和酪氨酸碘化作用的机制方案。
