Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA.
Toxicol Appl Pharmacol. 2012 Apr 1;260(1):81-8. doi: 10.1016/j.taap.2012.01.029. Epub 2012 Feb 8.
Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2 h) and was sustained in both rat (24-48 h) and human (24 h) with ≥ 10 μM MMI. Thyroid from rats treated with single doses of MMI (30-1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (~15-84 μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24h with MMI (≥ 10 μM) and PTU (100 μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ~2-fold) and only at higher MMI concentrations (≥ 1500 μM, 24h). Extended exposure (48 h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue.
采用大鼠甲状腺叶或人甲状腺切片的器官型模型评估药物诱导的甲状腺效应，以比较啮齿动物和人类的反应。甲状腺过氧化物酶 (TPO) 功能的抑制导致甲状腺激素合成和释放途径中的关键基因表达失调。临床使用的硫脲类药物甲巯咪唑 (MMI) 和 6-正丙基-2-硫代尿嘧啶 (PTU) 用于评估这些模型中的甲状腺药物反应。TPO 的抑制作用在大鼠甲状腺叶中很早就出现（2 小时），并在大鼠（24-48 小时）和人（24 小时）中持续存在，最低有效浓度为 10 μM MMI。单次给予 MMI（30-1000 mg/kg）的大鼠甲状腺持续 48 小时 TPO 抑制。大鼠体内 MMI 甲状腺浓度与培养浓度相当（~15-84 μM），因此表明体内和体外甲状腺效应之间存在密切相关性。在大鼠甲状腺叶中观察到 TPO 抑制的代偿反应，与甲状腺激素合成途径（Tpo、Dio1、Slc5a5、Tg、Tshr）和 megalin 释放途径（Lrp2）相关的基因显著上调，24 小时时 MMI（≥10 μM）和 PTU（100 μM）。同样，大鼠体内研究的甲状腺也表现出 Dio1、Slc5a5、Lrp2 和 Tshr 的上调。在人甲状腺切片中，少数基因表达发生变化（Slc5a5，约 2 倍），且仅在更高的 MMI 浓度（≥1500 μM，24 小时）下。延长暴露（48 小时）导致 Tpo、Dio1 和 Lrp2 以及 Slc5a5 和 Tshr 的上调。总之，在大鼠和人组织中，MMI 的浓度相似地抑制了 TPO，但大鼠对药物治疗的敏感性增加，这表明在不影响人组织的浓度下，甲状腺激素合成和释放基因途径的上调。
