In vitro investigations of the direct effects of complex anions on thyroidal iodide uptake: Identification of novel inhibitors
In vitro investigations of the direct effects of complex anions on thyroidal iodide uptake: Identification of novel inhibitors
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DOI：
10.1016/0887-2333(95)00114-x
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发表时间：
1996-04-01
影响因子：
3.2
通讯作者：
Barratt, MD
中科院分区：
文献类型：
--
作者：
Jones, PA;Pendlington, RU;Barratt, MD
甲状腺细胞从血浆中对化学和电梯度的碘摄取（IU）是通过特定的碘转运蛋白或“泵”进行的。高氯酸盐（ClO 4-）和其他单价对称阴离子是碘吸收（IU）的竞争性抑制剂，单个阴离子的表观Ki可与离子大小相关。本研究使用培养的甲状腺细胞和广泛的阴离子大小，特别是一系列的球形六氟离子，以了解更多关于IU的竞争性抑制剂的活性的参数。将培养的猪甲状腺细胞的I-125摄取和有机化与甲状腺过氧化物酶的生化酶抑制研究相结合，以确定对IU的特异性影响。在验证阶段使用了已知的抑制剂，并证明体外甲状腺细胞I-125测定和甲状腺过氧化物酶抑制测定的组合可用于鉴定难以单独使用甲状腺细胞鉴定的选择性抑制剂。体积小于或类似于I-（35.0埃（3））的阴离子是弱抑制剂，其效力与离子大小成比例增加，直到AsF 6-（94.45埃（3））的表观最大值;这种相关性很强（r = 0.96）。PF 6-、AsF 6-和SbF 6-被鉴定为IU的新型抑制剂，表明在IU抑制中具有活性的阴离子的尺寸范围大于先前鉴定的。六氟离子的抑制作用在体内的生物学意义尚不清楚。本研究中它们的效力表明，如果它们全身可用，这些阴离子可能有可能影响体内甲状腺功能。版权所有（C）1996 Elsevier Science Ltd.
Iodide uptake (IU) by thyrocytes from the plasma against chemical and electrical gradients is by a specific iodide transporter or 'pump'. Perchlorate (ClO4-) and other univalent, symmetrical anions are competitive inhibitors of iodide uptake (IU), and apparent K-i for individual anions can be correlated with ion size. This study uses cultured thyrocytes and a broad range of anion size, in particular a series of spherical hexafluoride ions, in order to understand more about the parameters governing the activity of competitive inhibitors of IU. I-125 uptake and organification by cultured porcine thyrocytes was combined with biochemical enzyme inhibition studies on thyroid peroxidase in order to identify specific effects on IU. Known inhibitors were used in a validation phase and demonstrated that a combination of the in vitro thyrocyte I-125 assay and thyroid peroxidase inhibition assay could be used to identify selective inhibitors that can be difficult to identify using thyrocytes alone. Anions of less than, or similar, volume to I- (35.0 Angstrom(3)) were weak inhibitors with potency increasing proportional to ion size up to an apparent maximum for AsF6- (94.45 Angstrom(3)); this correlation was strong (r = 0.96). PF6-, AsF6- and SbF6- were identified as novel inhibitors of IU, showing that the size range of anions active in IU inhibition is greater than that previously identified. The biological significance in vivo of the inhibitory action of the hexafluoride ions is not known. Their potency in this study suggests that these anions may have the potential to affect thyroid function in vivo if they were available systemically. Copyright (C) 1996 Elsevier Science Ltd.