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Iodine is an important micronutrient ,which has many functions associated with metabolism. Iodine is an essential factor in the synthesis of thyroid hormone (Roberts & Ladenson, 2004). Bernard Courtois in 1811 discovered Iodine during his invention of the gunpowder (Hetzel & Glugston, 1998). It is primarily present in soil,but wind,floods and sea leached the surface of the earcth from Iodine. (Hetzel & Clugston, 1998).Hence most parts of the world are iodine deficient because the soil is a poor source of iodine. The most important source of natural iodine is sea water.In the U.S., iodized table salt is the most common source of iodine in the diet. One gram of sodium chloride (NaCl) contains 74 mcg of iodine (Abraham, Flechas, & Hakala, 2002). Many people are on controlled diets for various reasons such as hypertension etc. and have eliminated iodised salt from their diets,as sodium is thought to be responsible for hypertension. Egg is also restricted by people due to its high cholesterol content,which if found to be detrimental in heart disease. Many people are simply choosing to drink more sodas in place of milk,which is also another important source of iodine. The recommended intake for iodine is 150 mcg per day for adults and 200 mcg per day for pregnant or lactating women. Because 90% of iodine is excreted in the urine, the best way to determine adequacy in nutrition is by testing urine iodine concentration by iodine loading test.
Main role of iodine in the body is as an important part of the thyroid hormones that regulate body temperature, metabolic rate, reproduction, growth, blood cell production, nerve and muscle function, and more (Whitney & Rolfes, 2005). Iodine is present in the thyroid in different forms; inorganic iodine, monoiodothyronine [MIT], diiodothyronine [DIT], 3,5,3'- triiodothyronine [T3], and thyroxine [T4], 3,5,3'5'-tetraiodothyronine. It is also prenet in the polypeptides containing thyroxine, and in thyroglobulin, which is a protein containing iodinated amino acids. Thyroglobulin is a glycoprotein ,which is the main storage form of the thyroid hormones containing approximately 90% of the total iodine in the thyroid gland (Hetzel & Clugston, 1998). Thyroid hormones are synthesized from iodine within the thyroid gland. This is done first by the thyroid trapping approximately 60 mcg of iodine per day to maintain an adequate supply of T4. Thyroid stimulating hormone (TSH) is a hormone from the pituitary gland that regulates an iodine pump. The iodine pump is an active transport mechanism, requiring energy, which allows iodine into the colloid follicle space between the thyroid cells, where it is oxidized by hydrogen peroxide. Then it forms monoiodothyronine[MIT] and diiodothyroinine[DIT] by coupling with tyrosine in the thyroglobulin. Next, a coupling reaction occurs with MIT and DIT to form the iodotyrosines. Finally, the iodinated thyroglobulin is absorbed back into the thyroid cells by pinocytosis. In the thyroid cells, proteolytic enzymes act on the thyroglobulin to release T4 and T3 into the blood. T4 is released to the target tissues that need it. Upon reaching the cells, T4 is deiodinated to T3, which is the active form of the hormone (Whitney & Rolfes, 2005). The hypothalamus regulates the secretion of T3 and T4 by controlling the release of the pituitary's TSH (Whitney & Rolfes, 2005). TSH secretion is controlled by a feedback mechanism closely related to the level of T4 in the blood (Hetzel & Clugston, 1998). When the T4 level falls, TSH secretion increases to increase thyroid activity to put more T4 into circulation. If there is not enough iodine to synthesize T4, then the T4 level remains low and the TSH level rises.
During digestion, iodine is rapidly absorbed through the gut (Hetzel & Clugston, 1998). The main part of iodine being absorbed into the blood from the intestines is in the form of iodide. The speed of iodine absorption is directly related to the quantity of its sources. Iodine compounds, such as iodinated fatty acids, are the most easily absorbed, along with inorganic salts, and organic iodine-containing substances such as thyroxin (T4) and diiodotyrosine (DIT) (Turakulov, 1959). The liver receives iodine from the portal vein and is able to regulate the passage of iodine into the blood circulation. This is necessary to avoid a large rise in serum iodine from an excessive quantity of iodine in foods consumed (Turakulov, 1959). Any excess iodine is excreted by the kidney. The amount of iodine excreted is directly proportional to the amount of iodine consumed, so this is one way to assess the level of iodine intake (Hetzel & Clugston, 1998).
Sodium Iodide symporter
THE SODIUM IODIDE SYMPORTER (NIS) is a membrane glycoprotein that mediates active iodide uptake in the thyroid gland and several extrathyroidal tissues. After molecular cloning of NIS, its structure and function were characterized, and factors affecting its expression/activity have been investigated (for review, see Jhiang  and Vieja et al. ). NIS is believed to span the plasma membrane 13 times, exhibiting an extracellular NH2 terminus and a cytosolic COOH terminus. Even though the degree of NIS glycosylation appears to be different among different tissues, there are no studies showing that this alters the function and stability of NIS. Although the exact mechanisms remain to be elucidated, several hydroxy-containing amino acid residues located in transmembrane segment IX (Ser-353, Thr-354, Ser-356, Thr- 357) appear to play an important role in NIS activity (2). Electrophysiological analysis of NIS indicates that a 2:1 sodium iodide (Na1/I2) stoichiometry, which results in a steadystate inward current, is induced by a net influx of Na1. Based on kinetic studies, NIS appears to be bound by Na1 before it is bound by I2. However, perchlorate, the best-characterized NIS inhibitor, appears to act as a blocker rather than as a competitive substrate.[ Sodium Iodide Symporter in Health and Disease]
Tissue Distribution of NIS
Radioiodine is commonly used to destroy overactive thyroid follicular cells in patients with Graves' disease or toxic nodular goiter, to reduce the size of large euthyroid multi-nodular goiters, to ablate normal and malignant thyroid tissues in patients who have undergone total thyroidectomy for papillary or follicular thyroid carcinoma, and to perform whole-body scans to detect recurrent and metastatic thyroid cancers. However, radioiodine uptake, as well as NIS expression, is not restricted to thyroid tissues. Radioiodine uptake by extrathyroidal tissues not only contributes to unwanted side effects of radiation, but it also contributes to difficulty in distinguish incidental findings on diagnostic scintigraphy, such as thymus uptake, from true metastatic thyroid lesions. Therefore, it is of clinical importance to determine the tissue distribution of NIS expression. Prior to its molecular cloning, the possible tissue distribution and cellular localization of NIS were indicated by studies of radioiodine biodistribution in laboratory animals as well as in human nuclear medicine studies using radioiodine or 99mTc pertechnetate (a known substrate of NIS) for scintiscans. In addition to thyroid tissues, uptake of radioiodine or 99mTc pertechnetate is almost always found in the salivary glands, stomach, lactating breast, nasal mucosa, and the placenta (although radioiodine should not be given during pregnancy). However, TSH only stimulates radioiodine uptake in thyroid tissues but not in these extrathyroidal tissues because of their absence of TSH receptors. Occasionally, radioiodine uptake is also seen in the nonlactating breasts of women (9). Radioiodine secretion in tears and the supraorbital uptake of 99mTc pertechnetate in patients without eye disorders suggest that active iodide uptake might also occur in the lacrimal glands (10). Other extrathyroidal tissues that take up radioiodine are hair follicles (11) and thymus (12,13). Tissue distribution of NIS mRNA has been investigated by Northern blot analysis, RNase protection assay, and reverse transcription-polymerase chain reaction (RT-PCR). Using NIS antibodies to identify its immunohistochemical cellular localization, NIS protein has been demonstrated in the salivary glands, stomach, lactating breast, lacrimal glands, and thymus. NIS expression is also found by RT-PCR in many other extrathyroidal tissues that are not known to concentrate radioiodine in vivo (1,2). Because RT-PCR is a sensitive method that detects low levels of NIS mRNA in a cell population, the clinical significance of NIS expression in these tissues requires further investigation. It is possible that the limited resolution of conventional scintiscans using a gamma camera is too insensitive to detect radioiodine in these tissues. Extrathyroidal tissues that minimally take up radioiodine are more likely to be identified using 124I positron emission tomography (PET). Ideally, the internal radiation dose for nonthyroidal tissues should be estimated to evaluate the possibility of radiation injury when radioiodine is administrated for clinical purposes.
Radioiodine uptake occurs in lactating breasts, and in some cases can be more pronounced than that in a normal thyroid remnant (67). We found immunohistochemical staining for NIS was mainly on the basolateral membrane of alveolar cells and the small ductal epithelial cells in the lactating mammary gland (68). This supports the notion that iodide is transported from blood to alveolar and small ductal cells, then moved to the lumen where milk is accumulated and secreted. However, neither breast feeding nor high serum prolactin levels are required for radioiodine uptake in breasts (9,69), and bromocriptine fails to alter uptake in nonlactating breasts (9). An animal study showed that the male mammary gland may also take up 99mTc pertechnetate provided gynecomastia is induced by medroxyprogesterone acetate (70). In humans, inflammation (mastitis) and benign nonproliferative fibrocystic disease induce radioiodine uptake in breasts (69). It is also noteworthy that the nonlactating breast has a relatively large capacity for iodide uptake (or rapid turnover of iodide), as its uptake is not suppressed by iodinated contrast media (9). Although radioiodine breast uptake was found in only about 6% of nonbreast-feeding women, it can be misinterpreted as thyroid cancer lung metastases if it presents with an atypical pattern or is clinically unexpected (9). The mechanism(s) of breast radioiodine uptake in nonlactating women may be different from those of lactating women. Nevertheless, significantly increased radioiodine uptake in the lactating breast suggests that radioiodine uptake and NIS expression are subjected to hormonal control (68,71). Therefore, patients with breast cancer might benefit from radioiodine therapy if NIS expression/ activity can be increased in the malignant tissues to levels sufficient for therapy. Radioiodine uptake is increased in mouse breast tissues that show atypia or malignancy (72). One study in mice indicates that high iodide uptake may prove to be the most specific biochemical characteristic of hormone-dependent breast tumors compared to hormone-independent tumors (73). Furthermore, NIS expression and radioiodine uptake were demonstrable in two different transgenic mouse mammary tumors (71). Indeed, some human breast cancers can be detected by radionuclide scintigraphy (74,75). A recent study (71) and unpublished data from our collaborative study indicate that NIS expression is detectable by immunohistochemical staining in some human breast cancers. Taken together, these findings indicate that NIS expression is increased in lactating breast tissues and in some breast tumors as compared with normal nonlactating breast. Analogous to thyroid cancers undergoing intensive TSH stimulation, under optimal stimulation of currently unknown hormone(s), radioiodine might be used both as a diagnostic test and for therapy of breast cancer. However, NIS expression in breast tissues appears to be driven by a combination of hormonal factors. We and others have shown that mammary gland NIS expression is regulated by prolactin and oxytocin (68,71). Retinoic acid also stimulates NIS expression and radioiodine uptake in a breast cancer cell line, MCF-7 (51). However, the increase in mammary NIS expression/ activity induced by drugs and hormones is not comparable to that induced by TSH in thyroid tissues. A thorough understanding of the hormonal regulation of NIS expression/activity in breast tissues is required before an optimal regimen of its hormonal stimulation can be developed to explore the possibility of radioiodine therapy of breast cancer. At the same time, it will be important to investigate whether the selected drugs/hormones stimulate tumor growth. .[ Sodium Iodide Symporter in Health and Disease]
the receptor shows increased expression (mainly intracellular) in malignant cells of different origin . These data suggest a role for iodine in the pathogenesis of cancer/apoptosis. It was recently shown that the iodine molecule itself induces apoptosis in human breast carcinoma cells involving a mitochondrial mediated pathway. In normal cells this effect could not be assessed . In case of iodine deficiency these processesmay be disturbed, leading to disturbed apoptosis and eventually to malignancies.
[Iodine deficiency, more than cretinism and goiter]
IODINE AND BREAST ANATOMY AND
In the mammal, iodide uptake has been demonstrated in various extrathyroidal tissues, including salivary gland, gastric mucosa, and the lactating mammary gland.10,11 Sodium iodide symporter (NIS) is the proteic trans- membrane transporter of iodide. Cloning and molecular characterization of the human NIS have been recently performed.12,13 The mammary gland has a high but temporary ability to concentrate iodides and to form iodocompounds9,14 in alveolar and ductular cells by speci®c peroxidases;15 this occurs almost exclusively during pregnancy and lactation, which are considered protective conditions against breast cancer. In fact, during pregnancy and lactation, hormonal stimulation of the breast leads to glandular differentiation with dramatically enhanced iodine adsorption and organi®- cation.14 It is interesting to note that this iodine adsorption occurs in the same ductal epithelium9,16,17 where the majority of breast cancers arise. Lactoper- oxidases, which are particularly active during pregnancy and lactation, organi®es iodide in the breast. According to Eskin,18 iodine plays an important role in the maintenance of both normal thyroid and breast physiology. Recently, a second pathway for iodine organi®cation has been described, which involves iodine incorporation into speci®c lipid molecules (polyunsaturated fatty acids). These iodolipids have been shown to be regulators of thyroid cell metabolism and proliferation. In particular, 6-iodo-5-hydroxy-eico- satrienoic acid (delta-iodolactone) has been found to be a potent inhibitor of thyroid cells proliferation19±21 and, according to Cann et al.9 these iodolipids may also play a role in anti-proliferative control of breast tissue. Tazebay et al.22 reported that expression of NIS in normal mammary tissues is stimulated by oxytocin, which is released during lactation. In ovariectomized rats, a combination of oestrogen, oxytocin and prolactin (PRL) led to maximal NIS expression in mammary cells. But what role does iodide play in mammary cells? We may chronologically differentiate2,4,5 on the basis of the phylogenesis and embryogenesis two possible mechan- isms of action of iodine:
1. The ®rst is more ancient with iodine acting directly on mammary cells which embryologically originate from iodide-concentrating ectoderm and epidermis, with iodide in mammary cells acting probably as antioxidant
2. The second mechanism of action is more modern, with iodine acting indirectly via thyroid hormones and their speci®c nuclear receptors. Hormonal imbalances can cause dysfunction of the mammary glands.
Rat mammary gland is able to take up (via NIS) and organically bind radioiodide. Iodination has not been detected in the mammary glands of non-pregnant rats. Protein-containing vacuoles in alveolar cells and casein-like proteins in milk are the major sites where iodination occurs within the gland. Milk proteins in the lumens of ductules adjacent to alveoli are also iodinated. Endogenous mammary peroxidases correlate with the ability to iodinate. In contrast, ducts, myoepithelial cells, fat cells, blood vessels and other histological components of the gland do not have this iodinating capability.
Eskin16 reported that iodine is a prerequisite for the normal development of breast tissue in higher verte- brates. When lacking, the parenchyma in rodents and humans show atypia, dysplasia, and even neoplasia; in fact, breast tissues are more susceptible to carcinogen action. In iodide-de®cient rats, Strum17 also reported atrophy, necrosis and areas of dysplasia and atypia occur in the mammary gland, which becomes highly sensitive to stimulation by oestradiol. In this way, oestradiol stimulates cell division and leads to the formation of alveoli with large quantities of lipid and protein droplets in large vacuoles which subsequently leads to the formation of cysts within the mammary gland. Eskin and coworkers18,23±26 reported a marked hyperplasia and papillomatosis of mammary ducts from rat given oestrogen in presence of disturbed thyroid± iodine metabolism and also a periductal ®brosis similar to that seen naturally in so-called ®brocystic disease of women. Dietary replacement therapy of iodine is able to improve these alterations in mammary tissue. Ghent et al.27 reported that 70% of women with ®brocystic breast disease treated orally with sodium iodide had clinical improvement in their breast disease. A decrease or loss of NIS expression may represent an early abnormality of thyroid28 and breast29 carcinogenesis rather than this occurring as a consequence of cancer progression. Statistical correlations between dietary iodine, thyroid diseases and breast cancer have been carried out by Ellerker,30 Stadel31 Serra-Majem et al.,32 Smyth et al.,33 Giani et al,34 Vassilopoulou-Sellin et al.35 and Cann et al.9 There is epidemiological evidence for the protective role against breast cancer of dietary ®sh (rich in iodine)36±39 and n-3 polyunsaturated fatty acids, in which speci®c double bonds are protected by iodine from peroxidation.6,7 Japanese women who have the highest iodine intake (4±10 mg/daily/per person) have the lowest rate of breast cancer mortality in the world. In fact, populations in Japan frequently eat a notable quantity of marine algae (seaweed), which is very rich in iodine,40,41 the RDA (recommended dietary allowance) of iodine is 150±200 mg per day. Recently, many researchers have studied NIS in mammary gland. Tazebay et al.22 reported that mammary NIS may be an essential breast cancer marker and that radioiodide should be studied as having a possible role in the diagnosis and treatment of breast cancer. Kilbane et al.42 demonstrated NIS expression in benign ®bro- adenomata and breast carcinoma, but total tissue iodine levels in benign tumours were signi®cantly higher than those in breast cancers taken from either tumour or morphologically normal tissue taken from within the tumour-bearing breast. Kogai et al.43 reported that NIS stimulates iodide uptake in normal lactating breast, but is not known to be active in nonlactating breast tissue or breast cancer. Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake into breast cancer cells. So, stimulation of radioiodide uptake after systemic retinoid treatment could be useful both in diagnosis and treatment of some differentiated breast cancers. Rillema et al.44 have shown that iodide accumulates in milk at higher concentration than in maternal plasma and that PRL enhances iodide accumulation 380 The Breast in cultured mammary tissues, via stimulation of NIS. Cho et al.45 suggested that iodine uptake and NIS expression in mammary gland are modulated by hormones involved in active lactation. NIS is clustered on the basolateral membrane of alveolar cells. The iodine uptake in the lactating mammary gland is partially inhibited by treatment with a selective oxytocin antagonist or bromocriptine, an inhibitor of PRL release.
IODINE AND THYROID HORMONE IN THE THERAPY OF BREAST DISEASES
Beatson46 reported adjuvant use of thyroid extract in some breast cancers in the Lancet as far back as 1896. Ghent et al.26 reported that iodine treatment of women with benign breast disease caused a signi®cant bilateral reduction in breast size, in addition to causing a remission of disease symptoms. Eskin and co-work- ers47,48 showed mammary tumour reduction in rats after iodine treatment. Some researchers have found that a seaweed-supplemented diet (rich in iodine) is associated with an inhibition and delay in the development of mammary cancer in rats.49±51 Funahashi et al. reported recently that both Japanese edible Wakame seaweed52 and direct uptake of inorganic iodine53 into a tumour experimentally suppress the effect of DMBA in inducing breast tumours grown in the rat. NIS expression is inversely related to undifferentiation, malignancy and is directly related to the likelihood of therapeutic effectiveness of radioiodine therapy. Recent studies have reported that genetic characterization and induction of the human NIS gene allows the development of a novel gene therapy treatment for extrathyroidal and mam- mary malignancies.54 In fact, targeted expression of functional NIS in undifferentiated cancer cells would enable these cells to concentrate iodine and would therefore offer the possibility of radioiodine therapy.55,56 Boland et al.57 proposed enlarging the therapeutic strategy of nonthyroid tumours by using an adenoviral vector to deliver NIS gene into the tumour cells for a targeted radiotherapy.
In conclusion, the thyroid is not the only organ known to organify iodide and to form iodocompounds. There is evidence for extrathyroidal iodide-concentrating organs, including the lactating breast and stomach. The knowledge of this iodinating ability and of the antioxidant and antitumour activity of iodide might be useful for helping to prevent breast cancer and also as a novel gene to allow radioiodine therapy to be given to patients with breast cancer.58 The extrathyroidal actions of iodide are an important new area for investigation
[Is there a role for iodine in breast diseases?]