Sodium iodine symporter

Recently, it has been shown that iodine, as well as 6-iodolactone, also inhibits the proliferation of mammary breast cancer cells (MCF-7) (Aceves et at, 2005). These cells express sodium iodine symporter (NIS) and lactoperoxidase, and therefore exhibit comparable machinery to metabofize iodine to 6-iodolactones fike thyroid cells. This is a new and exciting field, which might have implications for fmther examination into the role of iodine and 6-iodolactone in the treatment of breast cancer (Arroyo-Helguera et al., 2006). In fact Japanese women, with their high daily iodine intake, have a five-fold lower incidence of breast cancer breast cancer was treated in ancient years with high doses of iodine-containing algae. 

Perchlorate is an anion which inhibits the transfer of iodine into the thyroid gland and reduces the activity of the sodium iodine symporter. Thionamides, e.g., meth-yhnercaptoimidazole (MMI), block thyroid hormone production by inhibition of TPO-mediated iodination of tyrosine residues ofTg. 

It must be noted that IIH may occur with a latency of some weeks. Therefore, it is necessary to control thyroid hormones for an interval of 3—8 weeks after excessive iodine-load (Lawrence et al., 1999). Since perchlorate competes with iodine at the sodium iodine symporter, large doses of iodine may override the inhibitory effect of the usual doses of perchlorate recommended for the prophylaxis of IIH. 

EGER targeting was also used for systemic delivery of pDNA expressing the sodium iodide symporter (NIS) gene to liver cancer cells, followed by administration of radioactive isotope iodine-131, which accumulates in the tumor by NIS-mediated uptake in radiotherapeutic doses [227]. 

The perchlorate ion of potassium perchlorate, KCIO4, is a competitive inhibitor of thyroidal 1 transport via the Sodium Iodide Symporter (NIS).This drug can cause fatal aplastic anemia and gastric ulcers and is now rarely used. If administered with careful supervision, in limited low doses and for only brief periods, serious toxic effects can be avoided. The compound is especially effective in treating iodine-induced hyperthyroidism, which may occur, for example, in patients treated with the antiar-rhythmic compound amiodarone. Perchlorate ion can also be used in a diagnostic test of 1 incorporation into Tg, the so-called perchlorate discharge test. 

Uptake of Iodide. Dietary iodine reaches the circulation as iodide. Normally, its concentration in the blood is very low (0.2-0.4 ag/dL about 15-30 uM), but the thyroid actively transports the ion via a specific, membrane-bound protein termed the sodium-iodide symporter (NIS). The ratio of thyroid to plasma iodide concentration is usually between 20 and 50 and can far exceed 100 when the gland is stimulated. The NIS is inhibited by a number of ions such as thiocyanate and perchlorate (Figure 56-3). Thyrotropin (see below) stimulates the NIS, which is controlled by an autoregulatory mechanism. Thus, decreased stores of thyroid iodine enhance iodide uptake, and the administration of iodide can reverse this situation by decreasing NIS protein expression. 

The use of K1 serves as an important remedy to protect from radioiodine exposure under nuclear accident conditions. In principle, under normal circumstances, excess iodine decreases sodium—iodide symporter (NIS) on the thyroid cell surface, thereby inhibiting further access for iodine into the thyroid. Excess iodide administration at the appropriate time decreases thyroid radioactive iodine uptake (RAIU) by increasing the amount of nonradioactive... 

Cellular Iodine Transport Body Distribution of the Human Sodium Iodide Symporter... 

The expression of the sodium iodide symporter is perhaps nowhere more important than in the thyroid gland. A complete review of the physiological importance of the thyroid is beyond the scope of this chapter. It is sufficient to say that the symporter provides the iodine needed for normal thyroid function. Once the symporter has been trafficked to the basolateral surface of the thyrocyte, it can transport iodine from the blood into the cell. Once inside the cells, iodine is transported to the apical membrane where it is organified through attachment to a tyrosine residue and incorporated into the thyroid hormone thyroglobulin. The thyroglobu-lin is then stored inside thyroid follicles as colloid, to be released into the bloodstream as thyroid hormones (thyroxine and triiodothyronine) via TSH stimulation. 

The sodium iodide symporter transports iodine into the cell. 

Large amounts of thioq anate are generated in people with a high intake of cyanide from tobacco smoking, from cyanide in food, or from industrial pollution of the environment with cyanide. Thiocyanate may also be directly consumed with certain foods. Thiocyanate is a competitive inhibitor of the sodium iodide symporter (NIS) at thiocyanate levels normally found in blood. Thereby, it worsens iodine deficiency by inhibition of thyroidal iodide accumulation and by inhibition of iodide transport into breast milk for infant nutrition. Cessation of smoking, reduction of industrial pollution and improved diet will reduce the role of thiocyanate in thyroid disease. In individuals exposed to high levels of thiocyanate, adverse effects may be prevented by an increase in iodine intake. 

Perchlorate is a competitive inhibitor of the sodium-iodide symporter (NIS) and has been used in pharmacological doses to treat hyperthyroidism, especially iodine-induced hyperthyroidism. Perchlorate appears to be ubiquitous in the environment, and has been detected in trace amounts in the urine in almost all subjects evaluated both in the United States and Europe. In prospective clinical studies and environmental studies, there is no convincing evidence that environmental perchlorate adversely affects thyroid function. 

Figure 32.3 Inhibitory effects of iodide on human thyrocytes function, r, iodide NiS, sodium iodide symporter DUOX, duai oxidase TPO, thyroperoxidase TG, thyroglobulin TGI, iodinated thyroglobuiin X, the substrate converted into the active inhibitory iodinated molecule XI micro, micropinocytosis macro, macropinocytosis prolif, proliferation G.I., gene induction R, receptor Gs, stimulatory G protein of adenylyl cyclase AC, adenylyl cyclase cAMP, cyclic 3 -5 adenosine monophosphate PGE, prostaglandin E1 NE, norepinephrine Gq, stimulatory G protein of phospholipase C DAG, diacylglycerol IPS, inositol 1,4,5-trisphosphate Aa, amino acid ...

The extrathyroidal effects of iodine are of interest to physicians, due to its possible functions in many other organs. Iodine appears to be a vital trace element that is found in higher concentrations not only in the thyroid, but also in other tissues, such as salivary glands, lacrimal glands, stomach mucous membrane, plexus choroideus, lading mammary gland, pancreas, Langerhans islets and ciliar muscle of the eye. The distribution is not random, but it is related to the action of a specific active transport mechanism, the sodium iodide symporter (NIS). 

Radloiodlne Treatment Radioiodine therapy is particularly well-suited for the treatment of autonomously functioning thyroid tissue. Radioactive iodine, like the natural element, is taken up by the thyroid gland via an active process (the sodium iodide symporter) and accumulates within the thyroid gland. The therapeutic effect occurs as a result of tissue destruction (radiation thyroiditis) caused by short-reached (3 radiation detection is enabled due to emission of a small portion of irradiation. The radioactive material is selectively trapped by the more active autonomously functioning cells and, to a lesser extent, by normal thyrocytes, which depend on TSH stimulation to increase iodine uptake. 

Depletion of plasma iodide by following a diet with restricted iodine content is a complementary approach to the stimulation of thyroid tissue by endogenous or rTSH. Iodine depletion is thought to enhance radioiodine uptake and retention by thyroid tissue, by both increased expression of the sodium iodide symporter within thyroid cells (De La Vieja et al., 2000), and by reduced competition for uptake due to a reduced plasma iodide concentration. 

Figure 101.2 Thyroid iodide transport and organification. A schematic of a thyroid follicular cell showing the key aspects of thyroid iodine transport and thyroid hormone synthesis. TSHR, TSH receptor NIS, sodium iodide symporter TPO, thyroid peroxidase Tg, thyroglobulin.

The thyroid gland extracts iodine from the circulation and contains up to 90% of the total body iodine. The accumulation of iodine from the bloodstream to thyroid foUicles is mediated by a transmembrane transporter molecule called the sodium iodide symporter (NIS) (Dai et al., 1996). It is a membrane-bound glycoprotein with 13 transmembrane domains and is expressed on the basolateral membrane of thyroid follicular cells. 

Iodine plays a key structural role in the thyroid hormones of humans and other mammals, primarily in the form of T3 (triiodothyronine) and T4 (thyroxine). In such samples precursor forms such as MIT (monoiodotyrosine) and DIT (diiodotyrosine) or isomer forms such as rT3 (reverse triiodothyronine) may also be measured. Iodine accounts for 65% of the molecular weight of T4 and 59% of the T3.15-20 mg of iodine is concentrated in the thyroid and hormones with 70% distributed in other tissues. In the cells of these tissues, iodide enters via the sodium-iodide symporter (NIS). 

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