Shiroozu A, Taurog A, Engler H, Dorris M L
Endocrinology. 1983 Jul;113(1):362-70. doi: 10.1210/endo-113-1-362.
We have previously shown that the thioureylene antithyroid drugs 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) can inactivate thyroid peroxidase (TPO) in a model iodination system containing relatively high concentrations of iodide. The purpose of the present study was to determine whether these drugs may also inactivate TPO in vivo in rats. Assays for total TPO activity after injection of PTU or MMI did not prove to be a valid approach. As TPO inactivation might be expected to result in a relatively prolonged inhibition of enzyme activity, most of our experiments involved measurement of the duration of the inhibitory effect of a single injection of drug. Young rats were injected with low doses of PTU or MMI, and the effect on thyroidal organic iodine formation was determined at intervals after injection, either by 1-h pulse labeling with 131I- in vivo or by incubation of excised thyroid lobes in a medium containing 131I-. Results of both types of experiment demonstrated that the inhibitory effect of a small dose of PTU (1 mumol/100 g BW) was still very marked 17-18 h after injection. Moreover, an inhibitory effect of this small dose of PTU on the metabolism of [35S]MMI could also be demonstrated. Administration of MMI to rats, on the other hand, did not show the prolonged inhibitory effect observed with PTU. This is most likely attributable to the much lower thyroidal uptake of MMI than of PTU in rats. Intrathyroidal metabolism of [35S]PTU and [35S]MMI was also investigated. In contrast to the rapid disappearance of 35S from plasma, both drugs showed accumulation and retention of 35S in the thyroid. However, we obtained no evidence that thyroidal accumulation of PTU or one of its metabolites could explain the prolonged inhibitory effect of this drug. It seemed more likely that this was attributable to TPO inactivation. The clinical implications of our findings are discussed with relation to the dosage schedule commonly employed in the treatment of Graves' disease with antithyroid drugs.
我们之前已经表明，硫脲类抗甲状腺药物6-丙基-2-硫氧嘧啶（PTU）和1-甲基-2-巯基咪唑（MMI）在含有相对高浓度碘化物的模型碘化系统中可使甲状腺过氧化物酶（TPO）失活。本研究的目的是确定这些药物在大鼠体内是否也能使TPO失活。注射PTU或MMI后对总TPO活性的测定并未被证明是一种有效的方法。由于预计TPO失活会导致酶活性受到相对较长时间的抑制，我们的大多数实验都涉及测量单次注射药物的抑制作用持续时间。给幼鼠注射低剂量的PTU或MMI，并在注射后的不同时间间隔测定对甲状腺有机碘形成的影响，方法是在体内用131I进行1小时脉冲标记，或者将切除的甲状腺叶在含有131I-的培养基中孵育。两种类型实验的结果都表明，小剂量PTU（1 μmol/100 g体重）在注射后17 - 18小时的抑制作用仍然非常明显。此外，还可以证明这种小剂量PTU对[35S]MMI代谢有抑制作用。另一方面，给大鼠施用MMI并未显示出与PTU相同的长时间抑制作用。这很可能是由于大鼠甲状腺对MMI的摄取量远低于PTU。我们还研究了[35S]PTU和[35S]MMI在甲状腺内的代谢。与35S在血浆中迅速消失不同，两种药物在甲状腺中都显示出35S的积累和滞留。然而，我们没有证据表明PTU或其一种代谢产物在甲状腺中的积累可以解释该药物的长时间抑制作用。似乎更有可能是由于TPO失活。我们结合抗甲状腺药物治疗格雷夫斯病时常用的给药方案讨论了我们研究结果的临床意义。
