Characterization of small-molecule inhibitors of the sodium iodide symporter

Introduction

The synthesis of the iodide-containing thyroid hormones requires the active transport and accumulation of iodide from the blood into the thyroid gland that is mediated by the sodium/iodide symporter (NIS). The rat NIS sequence was the first to be identified (Dai et al. 1996), followed by the human (Smanik et al. 1996) and mouse sequences (Perron et al. 2001). The NIS is a glycoprotein residing in the basolateral membrane of thyrocytes (Dohan & Carrasco 2003). NIS catalyzes the cotransport of one iodide ion together with two sodium ions. For this process, the inwardly directed favourable transmembrane sodium gradient that is maintained by the Na+/K+-ATPase provides the driving force necessary for the transport of iodide against its electrochemical gradient. Thus, iodide is concentrated in the thyrocytes by up to 40-fold with respect to the plasma. Iodide is then translocated across the apical membrane of the thyrocytes into the colloid where it is immediately oxidized and organified into thyroglobulin by the thyroid-specific enzyme thyroid peroxidase. The coupling of two iodinated tyrosyl residues within the same thyroglobulin leads to the formation of the precursor molecules of the thyroid hormones T3 and T4. These iodinated thyroglobulins are stored in the colloid until phagocytosis is induced by TSH or pituitary thyrotropin. After hydrolysis, T3 and T4 hormones are released on the basolateral side of the thyrocytes into the bloodstream.

NIS expression and sodium-dependent active iodide transport has also been found in gastric mucosa, salivary gland and lactating mammary gland (Cho et al. 2000, Tazebay et al. 2000). Similar to the thyroid, NIS function generates an important iodide uptake in these tissues. The presence of NIS but no active iodide accumulation was shown in brain, intestine, skin, testis and several other tissues (Perron et al. 2001, Dohan et al. 2003).

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NIS also transports various other monovalent anions including , , SCN− and (Eskandari et al. 1997) and different radioisotopes such as pertechnetate (Cho et al. 2000, Tazebay et al. 2000, Van Sande et al. 2003), perrhenate (Dadachova et al. 2002) and astatine (At−; Lindencrona et al. 2001). Perchlorate is the only known efficient competitive inhibitor of NIS activity. Due to the lack of currents in electrophysiological experiments it remained uncertain until recently whether perchlorate is a transported substrate or inhibits the NIS activity (Eskandari et al. 1997, Van Sande et al. 2003, Clewell et al. 2004). Tracer uptake measurements by Van Sande et al. (2003) with pertechnetate and perrhenate (two large anions that have a similar chemical structure as perchlorate) strongly suggested that perchlorate is translocated into the thyroid via electroneutral transport. Dohan et al. (2007) recently showed that is actively transported by NIS in mammary gland of lactating rats leading to its accumulation in the milk. Thus, the stoichiometry of the NIS-mediated sodium/anion symport depends on the translocated anion varying from 2:1 for iodide to 1:1 or 2:2 for perchlorate (Dohan et al. 2007).

Only few organic molecules showing an inhibitory effect on the iodide transport in NIS-expressing tissues have been described so far. Most of these molecules are also known as chloride channel blockers like diphenylamine-2-carboxylate (DPC) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB; Gerard et al. 1994) or as inhibitors of other sodium-dependent transporters like harmaline and a chemical related drug (Kaminsky et al. 1991). Inhibitors of the Na+/K+-ATPase, like ouabaine, should also lead to the inhibition of the NIS-mediated iodide transport. In this case, no direct interaction with NIS occurs. Inhibition of the Na+/K+-ATPase abolishes the inward sodium gradient that provides the energy necessary for the iodide translocation. To date, only dysidenin a toxin isolated from the marine sponge Dysidea herbacea has been reported to be a specific NIS inhibitor. Van Sande and collaborators (Van Sande et al. 1990, 2003) found that dysidenin rapidly and strongly inhibits iodide transport in thyroid slices, thyrocyte plasma membrane vesicles and NIS-expressing cell lines (FRTL-5, transfected COS-7). The authors suggest a direct interaction of dysidenin with the NIS iodide binding site.

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Specific NIS inhibitors should prove useful for the treatment of various thyroid diseases. For example, amiodarone is a powerful antiarrhythmic and thus, is used in an increasing number of cardiac disorders. But amiodarone is a heavily iodinated drug and its administration induces chronic iodine overload, which frequently causes hyperthyroidism requiring treatment with potassium perchlorate (Bartalena et al. 2004). Due to its only short-lived inhibitory effect frequent, high doses of perchlorate have to be administered causing various undesirable side effects like vomiting, fever and kidney dysfunction. This underlines the need for new NIS inhibitors that could be therapeutic alternatives for perchlorate treatment. NIS inhibitors could also replace perchlorate in the diagnostic of thyroid pathology using 123I scintigraphy and perchlorate depletion tests. They should also prove useful in the case of radioactive iodine contamination (Dayem et al. 2006). A successful strategy in this situation should be a specific inhibition of the NIS-mediated thyroid iodide uptake without simultaneously affecting the secretion and elimination of radioiodine already contained in thyroid hormone precursors. Since to date no specific NIS inhibitor is available, KI consumption is the only protective measure used against thyroid radioiodine accumulation. This treatment is effective mainly when given before or immediately after exposure which considerably reduces its possible application (Dayem et al. 2006).

We here describe an electrophysiological analysis of 10 organic molecules on the iodide-induced current in Xenopus oocytes expressing NIS. These molecules were previously selected (Lecat-Guillet et al. 2008) from a compound collection using a recently developed high-throughput screening method (Lecat-Guillet et al. 2007) for their inhibitory effect on the 125I− uptake in permanently NIS-transfected HEK-293 cells. These molecules were named ITB-1-ITB-10 for ‘Iodide Transport Blocker’ (Lecat-Guillet et al. 2008). In the present study, the inhibitory effect of these molecules on the iodide transport was analyzed for its rapidity, reversibility and specificity. The compounds show a high diversity in their possible mode of action.

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