Taurog A, Dorris M L, Hu W X, Guziec F S
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235-9041.
Biochem Pharmacol. 1995 Mar 1;49(5):701-9. doi: 10.1016/0006-2952(94)00505-g.
6-Propylthiouracil (PTU), a widely used antithyroid drug for the treatment of Graves' disease, is also a potent inhibitor of Type I iodothyronine deiodinase (ID-1). Inhibition of ID-1 was attributed initially to the formation of a mixed disulfide between PTU and a putative cysteine residue at the active site. It has been demonstrated recently that ID-1 is a selenium-containing enzyme, with selenocysteine, rather than cysteine, at the active site. It seemed possible, therefore, that the selenium analog of PTU (PSeU) might be a more potent inhibitor of ID-1 than PTU. To test this possibility, we developed a procedure for the synthesis of PSeU, and we compared PSeU and PTU as inhibitors of ID-1 in a test system containing 125I-rT3, rat liver microsomes, and dithiothreitol. Deiodinase activity was measured by the increase in 125I-iodide. PTU and PSeU were tested at 0.1, 0.3, 1 and 3 microM. Based on results of four separate experiments, the drugs were essentially equipotent as inhibitors of ID-1, although statistical analysis suggested that PSeU may be slightly more potent than PTU. PTU and PSeU were also compared for antithyroid activity in vivo and in vitro. As inhibitors of the catalytic activity of thyroid peroxidase (TPO), the two drugs were essentially equipotent in iodination and guaiacol assays involving measurements made shortly after the addition of H2O2. However, in in vivo experiments with rats, PSeU showed no appreciable inhibition of organic iodine formation in the thyroid, whereas PTU, as expected, was a potent inhibitor. The lack of inhibition of organic iodine formation in vivo by PSeU suggests that, unlike PTU, it is not concentrated by the thyroid gland. In an iodination system in which H2O2 was generated by glucose-glucose oxidase, both PTU and PSeU, when present at 10 microM, acted as reversible inhibitors of iodination. However, when the drug concentration was raised to 50 microM, TPO was inactivated and iodination was irreversibly inhibited. These results suggest that PTU and PSeU inhibit TPO-catalyzed iodination by similar mechanisms. Under the same conditions, the selenium analog of methimazole (another widely used antithyroid drug) does not inactivate TPO. It acts primarily as a reversible inhibitor of TPO-catalyzed iodination.
6-丙基硫氧嘧啶（PTU）是一种广泛用于治疗格雷夫斯病的抗甲状腺药物，也是I型碘甲状腺原氨酸脱碘酶（ID-1）的有效抑制剂。ID-1的抑制作用最初被认为是PTU与活性位点上一个假定的半胱氨酸残基形成了混合二硫键所致。最近有研究表明，ID-1是一种含硒酶，其活性位点上是硒代半胱氨酸而非半胱氨酸。因此，PTU的硒类似物（PSeU）可能是比PTU更有效的ID-1抑制剂。为了验证这一可能性，我们开发了一种合成PSeU的方法，并在含有125I-反式三碘甲状腺原氨酸、大鼠肝微粒体和二硫苏糖醇的测试系统中比较了PSeU和PTU作为ID-1抑制剂的效果。脱碘酶活性通过125I-碘化物的增加来测定。PTU和PSeU分别在0.1、0.3、1和3微摩尔浓度下进行测试。基于四项独立实验的结果，这两种药物作为ID-1抑制剂的效力基本相当，不过统计分析表明PSeU可能比PTU稍强一些。PTU和PSeU还在体内和体外进行了抗甲状腺活性比较。作为甲状腺过氧化物酶（TPO）催化活性的抑制剂，在加入过氧化氢后不久进行测量的碘化和愈创木酚测定中，这两种药物的效力基本相当。然而，在大鼠体内实验中，PSeU对甲状腺中有机碘形成没有明显抑制作用，而PTU正如预期的那样是一种强效抑制剂。PSeU在体内对有机碘形成缺乏抑制作用表明，与PTU不同，它不会被甲状腺浓缩。在由葡萄糖-葡萄糖氧化酶产生过氧化氢的碘化系统中，当PTU和PSeU浓度为10微摩尔时，二者均作为碘化的可逆抑制剂。然而，当药物浓度提高到50微摩尔时，TPO失活，碘化被不可逆抑制。这些结果表明，PTU和PSeU通过类似机制抑制TPO催化的碘化反应。在相同条件下，甲巯咪唑（另一种广泛使用的抗甲状腺药物）的硒类似物不会使TPO失活。它主要作为TPO催化碘化反应的可逆抑制剂。
