In vitro investigations of the direct effects of complex anions on thyroidal iodide uptake: Identification of novel inhibitors

Abstract Iodide uptake (IU) by thyrocytes from the plasma against chemical and electrical gradients is by a specific iodide transporter or ‘pump’. Perchlorate (ClO 4 − ) 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. 125 I 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 125 I 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 A 3 ) were weak inhibitors with potency increasing proportional to ion size up to an apparent maximum for AsF 6 − (94.45 A 3 ); this correlation was strong ( r = 0.96). PF 6 − , AsF 6 − and SbF 6 − 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.