Facebook Twitter Digg Reddit Linkedin StumbleUpon E-mail

Review Article

Metabolic Pathways of Tetraidothyronine and Triidothyronine Production by Thyroid Gland: A Review of Articles

Pakistan Journal of Biological Sciences: Volume 14 (1): 1-12, 2011

A.R. Mansourian

Abstract

Tetraidothyronine (T4) and Triiodothyronine (T3) are the two vital hormones in human metabolism produced by thyroid gland. The major pathways in thyroid hormone biosynthesis begin with iodine metabolism which occurs in three sequential steps: active iodide transport into thyroid followed by iodide oxidation and subsequent iodination of tyrosyl residues of thyroglobulin (Tg) to produce idotyrosines monoidotyrosine (MIT) and diiodothyrosine (DIT) on Tg. Oxidized iodine and tyrosyle residues which are an aromatic amino acids are integral part of T4 and T3. The thyroid iodine deficiency of either dietary, thyroid malfunction , or disorder of hypothalamus and pituitary to produce enough Thyroid Stimulating Hormone (TSH), eventually lead to hypothyroidism with sever side effects. Iodine oxidation is the initial step for thyroid hormone synthesis within thyroid, is mediated by thyroperoxidase enzyme (TPO), which itself is activated by TSH required for production of MIT and DIT. T4 and T3 are subsequently are synthesized on Tg following MIT and DIT coupling reaction. Thyroid hormones eventually produced and released into circulation through Tg pinocytosis from follicular space and subsequent lysozomal function, a process again stimulated by TSH. The production of T4 and T3 are highly regulated externally by a negative feed-back interrelation between serum T4, T3 and TSH and internally by the elevated iodine within thyroid gland. It is believed the extra iodine concentration within thyroid gland control thyroid hormones synthesis by inhibition of the TPO and hydrogen peroxide (H2O2) formation which is also an essential factor of iodine oxidation, via a complex mechanism. In healthy subjects the entire procedures of T4 and T3 synthesis re-start again following a drop in serum T4 and T3 concentration. On conditions of thyroid disorders, which caused by the distruption of either of above mechanisms, thyroid hormone deficiency and related clinical manifestations eventually begin to show themselves.

How to cite this article:

A.R. Mansourian , 2011. Metabolic Pathways of Tetraidothyronine and Triidothyronine Production by Thyroid Gland: A Review of Articles. Pakistan Journal of Biological Sciences, 14: 1-12.

DOI: 10.3923/pjbs.2011.1.12

URL: https://scialert.net/abstract/?doi=pjbs.2011.1.12

INTRODUCTION

Thyroid principally synthesis two physiochemical important hormones, thyroxin or tetraidothyronine and triidothyronine best known as T4 and T3, respectively.

The precursor of thyroid hormones is tyrosine an aromatic amino acid existed within the structure of thyroglobulin (Tg) a macro-protein containing 5000 amino acids including 115 tyrosine residues. T4 and T3 are in fact iodine-tyrosine-based hormones. Iodine substituted on the tyrosine residues of Tg, by a complex process mediated, by Thyroid Stimulating Hormone (TSH), which is a hormone synthesized within the pituitary gland by the action of Thyrotropin Releasing Hormone (TRH), a hypothamous hormone. TSH is a hormone initiating the entire metabolic pathways, to produce T4 and T3. The active iodide transport from blood circulation into thyroid occur by TSH in spit of much higher iodide concentration in the gland.

The iodine subsequently oxidized by peroxidase enzymes, which itself is activated by TSH. The oxidated iodine is located on the tyrosine residues of thyroglobulin molecule which are within the follicular space of thyroid gland. monidotyrosine (MIT) and diidothyrosine (DIT) are produced, if either one or two oxidized iodine atoms are substituted on the tyrosyle residue of tyrosine amino acids, respectively. The subsequent metabolic pathway on the thyroglobuline is the coupling reactions between MIT and DIT, to produce T4 and T3 on the Tg molecule. On condition of coupling of either two DIT or one DIT and one MIT on the thyroglobuline T4 and T3 are produced, respectively. Therefore the biochemical structure of T4 and T3 contain, 4 and 3 iodine atoms, respectively and in fact 4 in T4 and 3 in T3, designated the number of iodines existed within the structure of thyroid hormones.

Following the above metabolic pathways in the thyroid, the iodinated residues within the structure of thyroglobulin released after the Tg is digested by lysozomol enzymes. The end products of thyrglobuline cleavages, are, T4, T3 and uncoupled idoniated tyrosyle residues of DIT and MIT. T4 and T3 are released from thyroid into blood circulation subsequently. (Targovnik et al., 1995; Selmi and Rousset, 1988; Rousset and Mornex, 1991; Linke et al., 2002).

The DIT and MIT also cleaved and the iodine re-circulated into the new T4 and T3 synthesis as explained earlier (Haeberli et al., 1978; Fonlupt et al., 1997; Wollman and Ekholm, 1981; Berndorfer et al., 1996; Ercson, 1981; Marino and McCluskey, 2000; Pierce et al., 1985; Bernier-Valentin, et al., 1990; Alvino et al., 1995; Portmann et al., 1985).

The crucial role of iodine in T4 and T3 production: Iodine is an essential part of T4 and T3 and thyroid hormone biochemical structure principally based on tyrosyle residue and iodine, therefore thyroid hormone with no iodine is not considered a hormone and it is only a modified form of an amino acid called tyrosine. Iodine is a element required during various stage of life, starting from fetus life, neonate, childhood, adolescency up to elderly age, because it is the vital part of T4 and T3 the crucial hormones required for metabolism, but the extent and the severity of its deficiency varies at different stage accordingly (Mansourian and Ahmadi, 2010; Mansourian, 2010a, b). The iodine deficiency during fetus life most often accompanied with mental retardation (De-Escobar et al., 2000; Mansourian, 2010c; Shahmohammdi et al., 2008; Mansourian et al., 2010b). Although during the first trimester of pregnancy fetus is dependent on the maternal thyroid hormones which if is required it is supplied to the fetus via placenta but in the second trimester of the fetus life thyroid hormones is originated from the fetal itself and not from maternal blood (De-Escobar et al., 2000). When fetus thyroid hormones requirement relay on the fetal origin and when the dietary iodine which reaches the fetus thyroid maternal blood circulation by placenta it is not neither enough nor effective, iodinated oil and salts supplementation should be advised (Tonglet et al., 1992).

There are reports of prenatal mortality which is originated by iodine deficiency. It is reported the mortality rate decreased following iodine supplementation through iodized oil prescription (Pharoah and Connolly, 1987; Cobra et al., 1997; Delong et al., 1997). The iodine within either the dietary or therapeutic regiments is absorbed in the small intestine and subsequently reaches to the thyroid gland, through blood circulation. The iodine following absorption by the thyroid gland oxidized through the peroxidase which is activated by Thyroid Stimulating Hormone (TSH). The oxidized iodine finally added to the tyrosyle residues on the thyroglobulin. The iodinated tyrosyle residues in the thyroid partly converted into MIT and DIT. It is only after the oxidized iodine incorporated into the tyrosyle resides structure of thyroglobuline and some of the synthesised MIT and DIT coupled and converted to T4 and T3, the Tg is digested by the protease enzymes of lysozomal apparatus of thyroid gland, it is then T4 and T3 and uncoupled MIT and DIT are released into the thyrocytes spaces. Thyroid hormones following production in the thyroid gland released into blood circulation and later on if the body required, in peripheral tissue some of T4 converted to T3, due to the fact that the T3 biologically is potentially more active than T4. The released MIT and DIT lose their iodine’s, which can subsequently re-enter the oxidizing pathways to incorporate into Tg structure to produce thyroid hormones in new cycle of T4 and T3 formation (Cauvi et al., 2001).

Thyroid hormones following the physiological activity in peripheral tissues disintegrated and the released iodine is subsequently re-absorbed by the thyroid gland and incorporated into the Tg, to re- produce T4 and T3 if it is metabolically required.

The consequence of iodine deficiency on T4 and T3 production: Iodine deficiency and the side effects accompanied by major abnormalities, starting from early phases of life up to elderly age in both men and women. Females are more susceptible to iodine deficiency particularly during pregnancy (Mansourian et al., 2007; Mansourian, 2010b) as the pregnant women required an extra amount of thyroid, therefore an extra amount of iodine is required to produce the extra T4 and T3. It should be mentioned that iodine deficiency during fetus life is the direct consequence of iodine deficiency during pregnancy (Mansourian, 2010c). The lack of enough iodine within maternal circulation is associated with fetus brain damage (De-Escobar et al., 2004; Auso et al., 2004; Koibuchi and Chin, 2000; Chan and Kilby, 2000; Delange, 2000; Glinoer and Delange, 2000; Delange, 2001). The fetus brain most probably damaged by iodine deficiency which is an integral part of thyroid hormones which themselves are critically required for brain development, during fetus and also the hormones are strongly required for the brain growth and developments of neonates. The iodine’s are not only required for the proper function but also well being physical growth of fetus, neonate and children are depend on enough iodine supplementation, (Mansourian, 2010a; Dobbing and Sands, 1973; Montuori et al., 2000; Mansourian et al., 2010a; Mansourian, 2010b).

The prevalence of iodine deficiency is word-wide, the children worst affected are from Africa, followed by South East Asia and Eastern Mediterranean. The iodine deficiency also easily can be found in other part of the world including Europe and America. The prevalence of iodine deficiency is even worse in Europe among general population, (Maberly et al., 1981; Cao et al., 1994; Mansourian et al., 2010a; Mansourian, 2010b; Mansourian et al., 2007). There are various reports across the world on the urgent look at the status of iodine intake among children to prevent growth abnormality among them (Caldwell et al., 2005; Dobbing, 1974).

There are also some reports indicating iodine deficiency, eventually lead to infant mortality (Pharoah and Connolly, 1987; Cobra et al., 1997). This latter observation was reversed by iodine therapy and supplementation (Delong et al., 1997). The other vital iodine role, is that the thyroid hormone not only required for fetus brain development and prenatal period, but also the thyroid hormones are required for up two years of life for proper physical development of infant growth and children and they require higher amount of thyroid hormones and gradually the requirement reduced as the children getting older (Dobbing, 1974; Mansourian and Ahmadi, 2010).

Adult hypothyroidism due to lack of iodine with subsequent cardiovascular consequences due to elevated serum lipids and subsequent adverse effects such as arthrosclerosis and other related cardiovascular diseases are also reviewed (Mansourian et al., 2008; Mansourian, 2010b). The consequences of iodine deficiency and the subsequent thyroid hormone deficiency of adult population may not be similar to what happen to the neonate brain but other side effects on adults subjects are also disturbing and interfering with normal routine physiological of life (Mansourian et al., 2008; Mansourian 2010a). It should be also mentioned that in rare cases the elevated iodine can be a stimulating factor for thyroid hyperactivity in addition to other metabolic disorders but such thyroid disorders are not common and instead the bases for hyperthyroidism are other metabolic disorders including muddles, hyperplasia and (Mansourian, 2010d, e; Kotani et al., 1986).

The Thyroid Enzymes required for T4 and T3 Synthesis: The intra- cellular iodine concentration within the thyroid gland is 25 times more than the extra-cellular and the iodine actively transported into thyroid gland from blood circulation via Na/K pump which is itself activated by TSH.

The iodine following entry into thyroid, subsequently oxidized by the thyoperoxidase enzyme (TPO) within the thyroid gland. Thyoperoxidase is an oxidizing enzyme is used to covert the iodine into iodide with subsequent attachment to the tyrosyl residue of thyroglobuline molecule with eventual production of T4 and T3, according to pathways which was already explained. The thyroperoxidase activity is resided within thyrocytes cell membrane. Thyroperoxidase is an enzyme dependent on heme, an organic substance of tetrapyrol and iron atom in its center. The iron vacancy can be changed from 2 to 3 and reversibly from 3 to 2 and on doing this chemical reaction and simultaneous use of hydrogen peroxide (H2O2) as a co-substrate the iodine as reduced form converted to oxidized iodine. The heme structure in thyroperoxidase is the same structure as heme in hemoglobin, but in hemoglobin, the iron valancy should remain at 2 and on any condition in which the iron valance converted to 3, the meth-hemoglobin which is produced can no longer transfer the molecule of oxygen. Heme molecule is an integral part of thyroperoxidase and the enzyme activities completely relay on the presence of the heme group with the thyroperoxidase enzyme (Niepomniszcze et al., 1972; Portmann et al., 1985; Czarnocka et al., 1985).

Initially TPO was discovered from patients with thyroid auto-immune diseases and antibody is raised against TPO, with thyroid disorders (Ruf et al., 1987; Hamada et al., 1987; Kimura et al., 1987; Seto et al., 1987; Libert et al., 1987; Mansourian, 2010e). Thyroperoxidase gene expression is under the control of TSH which mediate its role through cyclic AMP (cAMP), (Fayadat et al., 1998; Alquier et al., 1989; De-Deken et al., 2000). Although thyroperoxidase is an intracellular enzyme, but its enzymatic activity is resided on the apical membrane within the thyroid gland (Bjorkman and Ekholm, 1992; Carvalho et al., 1996). Some factors are required for the enzymatic pathway of TPO, these are H2O2 as co-substrate and reduced nictoamid dinucleotide phosphate (NADPH) which is a co-enzyme produced through carbohydrate metabolism the pentose phosphate pathway (Carvalho et al., 1996; Nakamura et al., 1989; Dupuy et al., 1991; Kimura et al., 1995). The TPO activity is started in the presence of iodide and the H2O2 and the production of iodinated Tg occur through either one of the two postulated mechanisms related to peptide hormones, in here it is the phosphatidly inositol pathway (PI), which eventually increase the intracellular ionized calcium (Corvilain et al., 1994). Thyroid main function, which is the production of T4 and T3 depends to the enough concentration of H2O2 although the high H2O2 concentration itself can be harmful to be thyroid cell, but thyroid is adapted to it through thyroid comprehensive mechanism to protect the thyrocyte from aggressive behavior of high dosage of H2O2 (Dunn and Dunn, 2008). The molecular mechanism and pathway leading to the production of H2O2 is highly complex and extensive investigation have been carried out on it at cellular and molecular levels and there are huge genetical and chromosomal-studies to uncover the much complex system of H2O2 producing pathways (Muresan and Arvan, 1997; Mercken et al., 1985; Spiro, 1977; Lenarcie et al., 2000; Kim and Arvan, 1998; Ohyama et al., 1994).

These latter investigation highlights the critical requirement of a separate enzymatic activity, which is triggered by cAMP dependent pathway which through a protein-kinas activate the enzyme responsible for the production of H2O2 within thyrocytes is activated. In other word it can be stated that it is the activation of enzymatic reaction to activate the protein-kinas with subsequent H2O2 production which can ultimately activate the TPO enzyme resulting in iodine oxidation and MIT and DIT formation, by transferring oxidized iodine on the tyrosyl residues of Tg to produce MIT and DIT with eventual production of T4 and T3. TPO facilitate the coupling of MIT and DIT to produce T4 and T3 on the Tg. Finally through endocyticis and lyzosmal reactions thyroid hormone separated from Tg and released into thyroid intracellular medium prior to secretion into blood circulation (Targovnik et al., 1995). There are some genetic studies, uncovering the bases behind some congenital hypothyroidism, which concentrate on the failed mechanisms which are responsible for thyroid malfunction and mostly related to the mutation of proteins and enzyme involved in the H2O2 production, leading to thyroid hormone deficiency, caused by the absence of enough H2O2 which is a cofactor for iodide oxidation.This latter observation is an important and absolute requirement step prior to MIT and DIT synthesis on Tg and eventual MIT and DIT coupling pathways. (Medeiros-Neto et al., 1996; Consiglio et al., 1987; Spiro and Gorski, 1986; Yamamoto et al., 1984; Ohyama et al., 1994).

Thyroglobulin is macro- protein which facilitate the production of thyroid hormones and iodine storage: Thyroglobulin (Tg), is a macroprotein whithin the thyroid gland containing about 5000 amino acids with about 115 tryosyle residue, the unique amino acid which only can have the ability to accept oxidized iodine and be converted to MIT and DIT, with subsequent T4 and T3 production. Tg also can be also considered as storage protein for iodine in the from of MIT and DIT. These latter iodinated substances can be regarded as storing iodine molecule and they can release their iodine for re-cycling to be oxidized again and used subsequently in new enzymatic pathway to re- synthesis T4 and T3 in thyroid gland (Medeiros-Neto et al., 1996).

The apical cell membrane and luman border in thyroid gland, is the original site for the production of tyrosyle iodination and T4 and T3 synthesis and the iodinated Tg site of storage is the luman follicular space. Genetically chromosome "eight" is the site where Tg derived from. There are extensive studies in this area of research which can give wide information and enlighten the whole spectrum of this complex mechanism (Mendive et al., 2001; Ohtaki et al., 1981; Cahmann et al., 1977; Lamas et al., 1974).

As the nature of a macroprotein such as Tg dicatate there should be enough cysteine amino acid residues to provide a strong and unique structure such as Tg, through the disulfide formation of high energy bond, required for such a huge molecule to have a integrated and unique biochemical structure. (Johnson and Tewkesbury, 1942; Gavaret et al., 1980; Gavaret et al., 1981). There are studies indicating that, there are inter- relationship between TPO, H2O2 generating system at genetical level and in some reports it is indicated that H2O2 might be responsible for the Tg and TPO, gene expression at chromosomal level (Kim et al., 1984; Fassler et al., 1988; Lamas et al., 1989).

Post- transitionally other modification should take place prior to full operational of Tg as backbone of thyroid hormone producing mechanism . Glycosylation seems to be a crucial post-transitional step forward prior for full activation of Tg. In practical term Tg is a glycoprotein which contain carbohydrate with the ratio of 1:10 in molecular weight (Dunn et al., 1983, De-Vijlder et al., 1992). Carbohydrate is required for the complete folding of Tg as huge macroprotein in follicular space of thyroid. In this regard there are extensive studies, indicating thyroid disorder may happen due to either malformed or misplaced Tg with eventual loss of thyroid hormones synthesis capability within the gland. (Robbins et al., 1959; Gire et al., 1996; Boeynaems et al., 1995).

How, eventually Tg and iodine produce T4 and T3: As it was mentioned earlier, the oxidized iodine covalently binds on to the some of 115 tyrosyle residues of Tg and produce iodinated tyrosyl residues. The requirement for this enzymatic reaction subsided by thyroperoxidase enzyme and hydrogen peroxide as a co-substrate. The apical plasma membrane of follicle luman border line is the location where Tg is iodinated on tyrosil residues to produce MIT and DIT. The TPO enzyme in the iodinated Tg playing the corner stone playing a crucial role of meditation, by attaching to both ionized iodine and tyrosyle residue.It is subsequently accompanied by MIT production in first step followed by attaching two oxidized iodine to the tyrosyle residue molecule to produce DIT.

Other suggestions indicated that initially iodine binds to TPO and following oxidation of iodine by thyroperoxidase enzyme oxidized iodine-TPO complex bind on to tyrosyle residue of Tg to produce MIT and DIT on thyroglobulin.

Other idea based on the initial oxidation of iodine followed by attachment to the tyrosile residue with subsequent production of MIT and DIT is also suggested. Under any condition and proposal the oxidized from of iodine should be added to the some of tyrosyle residues on Tg to form MIT and DIT. Also it is reported that at any time only about 30% of all tyrosyle residues of Tg are participated in the iodination processes. There are also controversial argument as whether MIT and DIT are produced independently, or DIT are synthesized, following MIT initially is produced, and an oxidized iodine is added subsequently to synthesis MIT (Haeberli et al., 1978; Marriq et al., 1991).

T4 and T3 are produced following MIT and DIT coupling reactions: The final step prior to the release of thyroid hormone from thyroid through pinocytosis and lyzosomal function on the Tg is the coupling process of MIT and DIT and lysozmal function on the Tg, The coupling process of MIT and DIT on the Tg molecule can be as follow: [MIT+DIT => Triidothyronine(T3)] and [DIT + DIT => tetraidothyronine (T4)]. The reactions are catalyzed also by thyroperoxidase enzyme and the presence of hydrogen peroxide (H2O2) as a co-substrate (Ekholm, 1981; Dunn et al., 1982; Ofverholm and Ericson, 1984; Gerber et al., 1985; Herzog et al., 1992; Berndorfer et al., 1996; Virion et al., 1985).

The production site T3 and T4 on Tg is also on the apical plasma membrane of follicule luman border line. The production of MIT and DIT with subsequent coupling reaction to produce T3 and T4 have studied extensively and the one of main conclusion in various studies, indicated that T4 and T3 are produced on a regulated and homogenous distribution on the Tg molecule and not all the tyrosyle residues on Tg are iodinated simultaneously and again the iodine deficiency initially reduces the DIT with eventual reduction in T4 concentration (Alvino et al., 1995; Ercson, 1981; Marino and McCluskey, 2000; Pierce et al., 1985; Bernier-Valentin et al., 1990).

As a simple rule in thyroid gland, despite all complexity of thyroid hormones synthesis within the thyroid gland, it is the availability of iodine, which is considered to be the central dogma in T4 and T3 production within the thyroid gland (Consiglio et al., 1979).

Self-Regulation of thyroid in producing T4 and T3 by iodine: The main vital controlling systems on how the thyroid gland should work properly relay on the thyroid, and hypothalamus pituitary axes, which dictate the suitable and desirable production of Thyrotropin Releasing Hormone (TRH) with subsequent production of Thyroid Stimulating Hormone (TSH) and on conditions of any disruptions in either of the negative-feedback TRH-TSH-thyroid gland axes, other metabolic disorders such as autoimmunity to the thyroid, thyroid nodules, and cancer, all can alter the serum level of T4 and T3, leaving behind thyroid disorder enough to disrupt normal physiological life of affected persons (Mansourian 2010, a-e) . In addition to that the thyroid itself internally regulated the production of T4 and T3. The corner stone for the inhibition of thyroid hormone production is the excessive iodine concentration within the thyroid gland which can inhibit the enzymatic reactions responsible for thyroid hormone synthesis. This observation well- known as Wolff-Chaikoff effect (Wolff and Chaikoff, 1948; Corvilain et al., 2000). There are extensive studies and various proposals are offered in how extra iodine concentration in thyroid can prevent the T4 and T3 production in the gland. In one report it is indicated that extra iodine inhibit the TPO enzyme and prevent hydrogen peroxide formation, with subsequent disruption on thyroglobuline to be iodinated. On doing that, there is not nither coupling reactions nor thyroid hormones production (Consiglio et al., 1979), Other argues, that it is possible that elevated iodine within the thyroid gland, causes the iodination of some substances within the thyroid, such as lipids and convert the lipids into iodated lipids residues. The iodinated lipids complex in turn can interfere with the enzymatic system responsible for the production of hydrogen peroxide, a compound crucially is required for the oxidation of iodine through TPO prior to Tg iodination an essential step for thyroid hormone synthesis. (Marino et al., 2000; Lisi et al., 2003; Ericson and Engstrom, 1978; Engstrom and Ericson, 1981; Johanson et al., 1988; De-Vijlder et al., 1992).

The pathways of thyroid hormones secretion from thyroid gland: Following Tg iodination the iodinated Tg, consist of iodinated tyrosyle residues of MIT, DIT and thyroid hormones of T4 and T3. As it was stated earlier in the apical membrane, of luman border line enzymes and co-substrate are available enough to trigger the synthesis of MIT, DIT. This step followed by coupling of MIT and DIT into T4 and T3 Tg, which now remain into follicule luman. The theory behind the high concentration of Tg within the follicule of thyroid, derived from the observation that in the follicle luman high ionized calcium concentration can easily bind to the Tg molecule, which is mainly contain acidic group capable of binding electro-statically to ionized calcium. It means the inonized Calcium (Ca2+) and acidic protein which carrying negative charge interact with each other and produce a weak chemical bond. On paving the latter mechanism, thyroglobulin is conserved at high concentration in the follicle luman and provide the primary step for Tg iodination with eventual aim of T4 and T3 production on Tg molecule (Dunn and Dunn 1982a, b, 1988; Virion et al., 1981). Up till this point the Tg molecule containing idotyrosil residues of MIT, DIT and also thyroid hormones of T4 and T3 residues in the intra follicular space. It is reported that TSH can play a role to change the condition of iodinated Tg within follicular space (Dunn et al., 1991, 1996; Deme et al., 1978). On physiological requirement of body tissues and the regulation of basic metabolic rate and the crucial need of thyroid hormones, T4 and T3 should be released subsequently from the thyroid gland and reach the tissues most needed by the thyroid hormones, therefore T4, T3, MIT and DIT are released simultaneously, through Tg endocytosis from follicular space in intracellular region of thyroid cells and lysozomal reactions on Tg. Selmi and Rousset (1988). The Tg endocytosis is occurred through internalization, the process mainly vesicles facilitated mechanism itself and conducted by Thyroid Stimulating Hormone TSH (Rousset and Mornex, 1991). The latter mechanism is not a straight forward pathway and the final end point only achieved after the former vesicles converted to new orientation to facilitate the initial phase of endocytosis. The endocytic Tg subsequently go through different metabolic routes, with eventual, degradation by lysozomal reaction and the production of thyroid hormones of T4 and T3 with eventual release of thyroid hormone out of thyroid gland into the blood circulation. As one expect the entire process from iodine absorption from blood up to release of T4 and T3 into the circulation mediated, stimulated and regulated by TSH (Linke et al., 2002).

The ultimate fate of thyroglobuline in thyroid following T4, T3 production and the pathway of thyroglobulin presence in the blood circulation: There are extensive studies in this area of thyroid metabolism, which can be summarized as follow: 1) Part of internalized Tg by the process of endocytosis continue its metabolic pathway, to subsequent endocytic route, with eventual aim of lysozomal functions, followed by Tg disintegration, to provide T4 and T3. 2) There are Tg molecule containing either of low T4 and T3 concentration or hormone precursors, it seems that these forms of Tg returned back to the follicular lumen, by a vesicular translocation and finally reaching to the apical membrane. Tg also can eventually reaches the apical plasma membrane facilitated by the Golgi apparatus (Neve et al., 1970; Tietze et al., 1989l; Andersson et al., 1990).

The other possible mechanism is the transportation of Tg on the basolateral membrane location of thyrocytes which mediated by the vesicles formation in cytosol.

It is also reported that the Tg found within the plasma originated from this latter mechanism (Muresan and Arvan, 1998; Toyoda et al., 1992).

The Tg molecules which are supposed to be re-located back to the follicular domains, does this metabolic pathway through receptor mediated pathway due to low concentration of Tg. The receptor mediated metabolic pathway is not required for endocytosis of Tg in the initial step of thyroid hormone formation due to the high concentration of Tg (Rosenberg and Goswami, 1979; Medeiros-Neto and Stanbury, 1994; Ohtaki et al., 1967).

The postulated theory of receptor binding to immature Tg with low thyroid hormones residues seems to be an acceptable package for recycling the Tg back into the follicular lumens and it is occurred through the carbohydrate residues and back bone recognition of by the Tg receptor (Montuori et al., 2000; Druetta et al., 1998).

The Tg receptor, structurally can be either a sialogycoprotein or N-acetyl glucosamine which distinguish the immature Tg to be recycled. On other hand TSH stimulate the Tg internalization, with subsequent colloid substance, with eventual delivery to the lysozomal, reaction pathway. Most interestingly the whole process of latter pathway mediated by 2nd messenger of TSH hormone well known as cyclic adenosine monophosphate pathway cAMP. (Druetta et al., 1999; Spencer, 2000; Ladenson et al., 1997; Schlumberger et al., 2000; McDougall and Weigel, 2001).

The mature Tg macromolecules are brake down by enzymatic reaction of lysozome and eventually T4 and T3 are released. In producing thyroid hormones from Tg. various enzymes of hydrolytic nature, are involved. (Robbins et al., 2001; Wartofsky et al., 2002; Mazzaferri et al., 2003). Following Tg cleavage by lysozome and subsequent T4 and T3 release from Tg within the thyroid the hormones released into blood circulation. The passage of thyroid hormones from lysozomal membrane and subsequent secretion is not fully understand, but a thyroid hormone transporter in this pathway is postulated The release of free hormones into blood circulation and negative interrelation of serum T4 and T3 with TSH concentration is the corner stone for the control of T4 and T3 synthesis in the thyroid gland (Robbins et al., 2001; Wartofsky et al., 2002; Mazzaferri et al., 2003). In thyroid disorder such as hyperplastic thyroid, thyroid nodules and thyroid cancer, the serum Tg concentration is elevated. Serum Tg concentration is a valuable tool for the diagnosis of such thyroid disorder and an indicative of thyroid hyperactivity. Tg measurement can be a useful laboratory test for the identification of congenital and various multi-nodular goiters. The serum Tg assessments can also be used to follow the cycle and follow up of thyroid cancer (Druetta et al., 1999; Spencer, 2000; Schneider et al., 1983; Mazzaferri et al., 2003).

CONCLUSION

Tetraidotyronine(T4) and triidotyronine (T3) are the hormones synthesized in thyroid gland, on thyroglobulin macromolecule resided within the follicular space of thyroid. The oxidized iodine, which produced in thyroid, is added on thyrosyle residue of thyroglobulin, producing monoidothyrosine (MIT) and diidothyrosine (DIT),. T4 and T3 are synthesized following coupling of two latter iodinated tyrosyle residues on thyroglobulin and released from thyroid following thyroglobulin pinocytosis from follicular compartment and subsequent lysozomal biochemical enzymatic reaction on thyroglobulin.

Iodine is considered to be an integral part of T4 and T3, which is located on tyrosyle residues of thyroglobulin following oxidation in the thyroid gland by thyroperoxidase enzyme, itself activated by Thyroid Stimulating Hormone (TSH) a pituitary hormone responsible for thyroid function.Iodine deficiency eventually lead to reduced concentration of T4 and T3, which can have sever consequences particularly in fetus life up to elderly age.

Thyroperoxidase (TPO) enzyme is a thyroid enzyme activated by TSH, it is an oxidizing agent which can oxidize the iodine in the thyroid with cooperation of hydrogen peroxide (H2O2) a vital factor for this biochemical reaction. The iodine oxidation is crucial step prior to binding on tyrosyle residue on thyroglobulin and eventual production of T4 and T3.

The production of T4 and T3 essentially controlled through hypothalamus-pituitary axes and thyroid gland through a highly regulated negative-feedback mechanism. In healthy subjects in addition to negative feed-back relation between T4, T3 and TSH but there is, a self-regulatory system of T4 and T3 production within the thyroid gland is also existed. The excessive iodine concentration within thyroid gland in thyroid play a vital role in autonomous mechanism to control T4 and T3 synthesis through the inhibition of the thyroperoxidase enzyme reactions by the elevated iodine, with subsequent stoppage in T4 and T3 synthesis.

References

Alquier, C., J. Ruf, A.M. Athouel-Haon and P. Carayon, 1989. Immunocytochemical study of localization and traffic of thyroid peroxidase/microsomal antigen. Autoimmunity, 3: 113-123.
PubMed

Alvino, C.G., A.M.M. Catanzano and V. Tassi, 1995. Evidence that thyroglobulin has an associated protein kinase activity correlated with the presence of an adenosine triphosphate binding site. Endocrinol., 136: 3179-3185.
PubMed

Andersson, H.C., L.D. Kohn, I. Bernardini, H.J. Blom, F. Tietze and W.A. Gahl, 1990. Characterization of lysosomal monoiodotyrosine transport in rat thyroid cells. Evidence for transport by system h. J. Biol. Chem., 265: 10950-10954.
PubMed

Auso, E., R. Lavado-Autric, E. Cuevas, F.E. Del-Rey, G.M. De Escobar and P. Berbel, 2004. A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocoticogenesis alters neuronal migration. Endocrinology, 145: 4037-4047.

Berndorfer, U., H. Wilms and V. Herzog, 1996. Multimerization of thyroglobulin (TG) during extracellular storage: Isolation of highly cross-linked TG from human thyroids. J. Clin. Endocrinol. Metab., 81: 1918-1926.
Direct Link

Bernier-Valentin, F., Z. Kostrouch, R. Rabilloud, Y. Munari-Silem and B. Rousset, 1990. Coated vesicles from thyroid cells carry iodinated thyroglobulin molecules. J. Biol. Chem., 265: 17373-17380.
PubMed

Bjorkman, U. and R. Ekholm, 1992. Hydrogen peroxide generation and its regulation in FRTL-5 and porcine thyroid cells. Endocrinology, 130: 393-399.
PubMed

Boeynaems, J.M., J. van Sande and J.E. Dumont, 1995. Which lipids are involved in thyroid autoregulation: Iodolactones or iodoaldehydes. Eur. J. Endocrinol., 132: 733-734.
CrossRef

Cahmann, H.J., J. Pommier and J. Nunez, 1977. Spatial requirement for coupling of iodotyrosine residues to form thyroid hormone. Proc. Natl. Acad. Sci. USA., 74: 5333-5335.
Direct Link

Caldwell, K.L., R. Jones and J.G. Hollowell, 2005. Urinary iodine concentration: United States National health and nutrition examination survey 2001-2002. Thyroid, 15: 692-699.
PubMed

Cao, X.Y., X.M. Jiang, A. Kareem, Z.H. Dou and M.A. Rakeman et al., 1994. Iodination of irrigation water as a method of supplying iodine to a severely iodine-deficient population in Xinjiang, China. Lancet, 344: 107-110.
PubMed

Carvalho, D.P., C. Dupuy, Y. Gorin, O. Legue, J. Pommier, B. Haye and A. Virion, 1996. The Ca2+- and reduced nicotinamide adenine dinucleotide phosphate-dependent hydrogen peroxide generating system is induced by thyrotropin in porcine thyroid cells. Endocrinol., 137: 1007-1012.
PubMed

Cauvi, D., M.C. Nlend, N. Venot and O. Chabaud, 2001. Sulfate transport in porcine thyroid cells. Effects of thyroglobulin and iodide. Am. J. Physiol. Endocrinol. Metab., 281: 440-448.
PubMed

Chan, S. and M.D. Kilby, 2000. Thyroid hormone and central nervous system development. J. Endocrinol., 165: 1-8.
PubMed

Cobra, C., Muhilal, K. Rusmil, D. Rustama and Djatnika et al., 1997. Infant survival is improved by oral iodine supplementation. J. Nutr., 127: 574-578.
PubMedDirect Link

Consiglio, E., A.M. Acquaviva, S. Formisano, D. Liguoro and A. Gallo et al., 1987. Characterization of phosphate residues on thyroglobulin. J. Biol. Chem., 262: 10304-10314.
PubMed

Consiglio, E., G. Salvatore, J.E. Rall and L.D. Kohn, 1979. Thyroglobulin interactions with thyroid membranes. The existence of specific receptors and their potential role. J. Biol. Chem., 254: 5065-5076.
PubMed

Corvilain, B., E. Laurent, M. Lecomte, J. van Sande and J.E. Dumont, 1994. Role of the cyclic adenosine 3`,5`-monophosphate and the phosphatidylinositol-Ca2+ cascades in mediating the effects of thyrotropin and iodide on hormone synthesis and secretion in human thyroid slices. J. Clin. Endocrinol. Metab., 79: 152-159.

Corvilain, B., L. Collyn, J. van Sande and J.E. Dumont, 2000. Stimulation by iodide of H2O2 generation in thyroid slices from several species. Am. J. Physiol. Endocrinol. Metab., 278: 692-699.
PubMed

Czarnocka, B., J. Ruf, M. Ferrand, P. Carayon and S. Lissitzky, 1985. Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Lett., 190: 147-152.
CrossRef

De Deken, X., D. Wang, M.C. Many, S. Costagliola and F. Libert et al., 2000. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J. Biol. Chem., 275: 23227-23233.
Direct Link

De Escobar, G.M., M.J. Obregon and F.E. Del Rey, 2004. Role of thyroid hormone during early brain development. Eur. J. Endocrinol., 151: U25-U37.
CrossRefDirect Link

De Escobar, G.M., M.J. Obregon and F.E. del Rey, 2000. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia. J. Clin. Endocrinol. Metab., 85: 3975-3987.
CrossRefDirect Link

De Vijlder, J.J., G.J. Veenboer and J.E. Van-Dijk, 1992. Thyroid albumin originates from blood. Endocrinology, 131: 578-584.
Direct Link

Delange, F., 2000. Endemic Cretinism. In: The Thyroid. A Fundamental and Clinical Text, Braverman, L.E. and R.D. Utiger (Eds.). Lippincott, Philadelphia, PA., pp: 743-754.

Delange, F., 2001. Iodine deficiency as a cause of brain damage. Postgrad. Med. J., 77: 217-220.
PubMed

Delong, G.R., P.W. Leslie, S.H. Wang, X.M. Jiang and M.L. Zhang et al., 1997. Effect on infant mortality of iodination of irrigation water in a severely iodine-deficient area of China. Lancet, 350: 771-773.
PubMed

Deme, D., J. Pommier and J. Nunez, 1978. Specificity of thyroid hormone synthesis. The role of thyroid peroxidase. Biochim. Biophys. Acta, 540: 73-82.
CrossRef

Dobbing, J. and J. Sands, 1973. Quantitative growth and development of human brain. Arch. Dis. Child., 48: 757-767.
PubMed

Dobbing, J., 1974. The later growth of the brain and its vulnerability. Pediatrics, 53: 2-6.
PubMed

Druetta, L., H. Bornet, G. Sassolas and B. Rousset, 1999. Identification of thyroid hormone residues on serum thyroglobulin: A clue to the source of circulating thyroglobulin in thyroid diseases. Eur. J. Endocrinol., 140: 457-467.
PubMed

Druetta, L., K. Croizet, H. Bornet and B. Rousset, 1998. Analyses of the molecular forms of serum thyroglobulin from patients with Graves` disease, subacute thyroiditis or differentiated thyroid cancer by velocity sedimentation on sucrose gradient and Western blot. Eur. J. Endocrinol., 139: 498-507.
PubMed

Dunn, A.D. and J.T. Dunn, 1982. Thyroglobulin degradation by thiol proteases: Action of purified Cathepsin D. Endocrinol., 11: 280-289.

Dunn, A.D. and J.T. Dunn, 1982. Thyroglobulin degradation by thiol proteases: Action of thiol endopeptidases in vitro. Endocrinology, 111: 290-298.
PubMed

Dunn, A.D. and J.T. Dunn, 1988. Cysteine proteinasee from human thyroid and their actions on thyroglobulin. Endocrinology, 123: 1089-1097.
PubMed

Dunn, A.D., H.E. Crutchfield and J.T. Dunn, 1991. Thyroglobulin processing by thyroidal proteases. J. Biol. Chem., 266: 20198-20204.
PubMed

Dunn, A.D., H.E. Muers and J.T. Dunn, 1996. The combined action of two thyroid proteases releases T4 from the dominant hormone-forming site of thyroglobulin. Endocrinology, 137: 3279-3285.
PubMed

Dunn, J.T. and A.D. Dunn, 2008. Thyroglobulin: Chemistry, Biosynthesis and Proteolysis. In: The Thyroid, Braverman, L.E. and R. Utiger (Eds.). Lippincott Williams and Wilkins, Philadelphia, pp: 91-104.

Dunn, J.T., P.S. Kim and A.D. Dunn, 1982. Favored sites for thyroid hormone formation on the peptide chains of human thyroglobulin. J. Biol. Chem., 257: 88-94.
PubMed

Dunn, J.T., P.S. Kim, A.D. Dunn, D.G. Heppner and R.C. Moore, 1983. The role of iodination in the formation of hormone-rich peptides from thyroglobulin. J. Biol. Chem., 258: 9093-9099.
PubMed

Dupuy, C., A. Virion, R. Ohayon, J. Kaniewski, D. Deme and J. Pommier, 1991. Mechanism of hydrogen peroxide formation catalyzed by NADPH oxidase in thyroid plasma membrane. J. Biol. Chem., 266: 3739-3743.
PubMedDirect Link

Ekholm, R., 1981. Iodination of thyroglobulin. An intracellular or extracellular process. Mol. Cell. Endocrinol., 24: 141-163.
CrossRef

Engstrom, G. and L.E. Ericson, 1981. Effect of graded doses of thyrotropin on exocytosis and early phase of endocytosis in the rat thyroid. Endocrinology, 108: 399-405.
PubMed

Ercson, L.E., 1981. Exocytosis and endocytosis in the thyroid cell. Mol. Cell Endocrinol., 22: 1-24.
PubMed

Ericson, L.E. and G. Engstrom, 1978. Quantitative electron microscopic studies on exocytosis and endocytosis in the thyroid follicle cell. Endocrinology, 103: 883-892.
CrossRef

Fassler, C.A., J.T. Dunn, P.C. Anderson, J.W. Fox and A.D. Dunn et al., 1988. Thyrotropin alters the utilization of thyroglobulin`s hormonogenic sites. J. Biol. Chem., 263: 17366-17371.
PubMed

Fayadat, L., P. Niccoli-Sire, J. Lanet and J.L. Franc, 1998. Human thyroperoxidase is largely retained and rapidly degraded in the endoplasmic reticulum. Its N-glycans are required for folding and intracellular trafficking. Endocrinology, 139: 4277-4285.
Direct Link

Fonlupt, P., C. Audebet, V. Gire, F. Bernier-Valentin and B. Rousset, 1997. Calcium is transported into the lumen of pig thyroid follicles by fluid phase basolateral to apical transcytosis. J. Cell Physiol., 171: 42-51.
PubMed

Gavaret, J.M., H.J. Cahnmann and J. Nunez, 1981. Thyroid hormone synthesis in thyroglobulin: The mechanism of the coupling reaction. J. Biol. Chem., 256: 9167-9172.
PubMed

Gavaret, J.M., J. Nunez and H.J. Cahnmann, 1980. Formation of dehydroalanine residues during thyroid hormone synthesis in thyroglobulin. J. Biol. Chem., 255: 5281-5285.
PubMed

Gerber, H., H. Studer and C. von Grunigen, 1985. Paradoxical effects of thyrotropin on diffusion of thyroglobulin in the colloid of rat follicles after long term thyroxine treatment. Endocrinology, 116: 303-310.
PubMedDirect Link

Gire, V., Z. Kostrouch, F. Bernier-Valentin, R. Rabilloud, Y. Munari-Silem and B. Rousset, 1996. Endocytosis of albumin and thyroglobulin at the basolateral membrane of thyrocytes organized in follicles. Endocrinology, 137: 522-532.
PubMed

Glinoer, D. and F. Delange, 2000. The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid, 10: 871-887.
Direct Link

Haeberli, A., F.K. Millar and S.H. Wollman, 1978. Accumulation and localization of radiocalcium in the rat thyroid gland. Endocrinology, 102: 1511-1519.
PubMed

Hamada, N., L. Portmann and L.J. De-Groot, 1987. Characterization and isolation of thyroid microsomal antigen. J. Clin. Invest., 79: 819-825.
CrossRef

Herzog, V., U. Berndorfer and Y. Saber, 1992. Isolation of insoluble secretory product from bovine thyroid: Extracellular storage of thyroglobulin in covalently cross-linked form. J. Cell Biol., 118: 1071-1083.
PubMedDirect Link

Johanson, V., T. Ofverholm and L.E. Ericson, 1988. Forskolin-induced elevation of cyclic AMP does not cause exocytosis and endocytosis in rat thyroid follicle cells in vivo. Mol. Cell Endocrinol., 59: 27-34.
PubMed

Johnson, T.B. and L.B. Tewkesbury, 1942. The oxydation of 3,5-diiodotyrosine to thyroxine. Proc. Natl. Acad. Sci. USA., 28: 73-77.
PubMed

Kim, P.S. and P. Arvan, 1998. Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: Disorders of protein trafficking and the role of ER molecular chaperones. Endocr. Rev., 19: 173-202.
PubMed

Kim, P.S., J.T. Dunn and D.L. Kaiser, 1984. Similar hormone-rich peptides from thyroglobulins of five vertebrate classes. Endocrinology, 114: 369-374.
PubMed

Kimura, S., T. Kotani, O.W. McBride, K. Umeki, K. Hirai, T. Nakayama and S. Ohtaki, 1987. Human thyroid peroxidase: Complete cDNA and protein sequence, chromosome mapping and identification of two alternately spliced mRNAs. Proc. Natl. Acad. Sci. USA., 84: 5555-5559.
PubMed

Kimura, T., F. Okajima, K. Sho, I. Kobayashi and Y. Kondo, 1995. Thyrotropin-induced hydrogen peroxide production in FRTL-5 thyroid cells is mediated not by adenosine 3',5'monophosphate, but by Ca2+ signaling followed by phospholipase-A2 activation and potentiated by an adenosine derivative. Endocrinology, 136: 116-123.
PubMed

Koibuchi, N. and W.W. Chin, 2000. Thyroid hormone action and brain development. Trends Endocrinol. Metab., 4: 123-128.
CrossRef

Kotani, T., K. Umeki, S. Matsunaga, E. Kato and S. Ohtaki, 1986. Detection of autoantibodies to thyroid peroxidase in autoimmune thyroid diseases by micro-ELISA and immunoblotting. J. Clin. Endocrinol. Metab., 62: 928-933.
Direct Link

Ladenson, P.W., L.E. Braverman, E.L. Mazzaferri, F. Brucker-Davis and D.S. Cooper et al., 1997. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N. Engl. J. Med., 337: 888-896.
PubMed

Lamas, L., A. Taurog, G. Salvatore and H. Edelhoch, 1974. The importance of thyroglobulin structure i thyroid peroxidase-catalyzed conversion of diiodotyrosine to thyroxine. J. Biol. Chem., 249: 2732-2737.

Lamas, L., P.C. Anderson, J.W. Fox and J.T. Dunn, 1989. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J. Biol. Chem., 264: 13541-13545.
PubMed

Lenarcie, B., G. Krishnan, R. Borukhovich, B. Ruck, V. Turk and E. Moczydlowski, 2000. Saxiphilin, a saxitoxin-binding protein with two thyroglobulin type1 domains, is an inhibitor of papain-like cysteine. J. Biol. Chem., 275: 15572-15577.
PubMed

Libert, F., J. Ruel, M. Ludage, S. Swillens, N. Alexander, G. Vassart and C. Dinsart, 1987. Thyroperoxidase, an auto-antigen with a mosaic structure made of nuclear and mitochondrial gene modules. EMBO J., 6: 4193-4196.
PubMed

Linke, M., V. Herzog and K. Brix, 2002. Trafficking of lysosomal cathepsin B-green fluorescent protein to the surface of thyroid epithelial cells involves the endosomal/lysosomal compartment. J. Cell Sci., 115: 4877-4889.
PubMed

Lisi, S., A. Pinchera, R.T. McCluskey, T.E. Willow and S. Refetoff et al., 2003. Preferential megalin-mediated transcytosis of low hormonogenic thyroglobulin: A control mechanism for thyroid hormone release. Proc. Natl. Acad. Sci. USA., 100: 14858-14863.
PubMed

Maberly, G.F., C.J. Eastman and J.M. Corcoran, 1981. Effect of iodination of a village water-supply on goitre size and thyroid function. Lancet, 318: 1270-1272.
CrossRef

Mansourian, A.R. and A.R. Ahmadi, 2010. Correlation between inverse age and serum thyroxine level among children and adolescents. J. Clin. Diagn. Res., 4: 3196-3200.
Direct Link

Mansourian, A.R., 2010. A review on hyperthyroidism: Thyrotoxicosis under surveillance. Pak. J. Biol. Sci., 13: 1066-1076.
CrossRefDirect Link

Mansourian, A.R., 2010. The immune system which adversely alter thyroid functions: A review on the concept of autoimmunity. Pak. J. Biol. Sci., 13: 765-774.
CrossRefDirect Link

Mansourian, A.R., 2010. A review on post-puberty Hypothyroidism: A glance at myxedema. Pak. J. Biol. Sci., 13: 866-876.
CrossRefDirect Link

Mansourian, A.R., 2010. The state of serum lipids profiles in sub-clinical hypothyroidism: A review of the literature. Pak. J. Biol. Sci., 13: 556-562.
Direct Link

Mansourian, A.R., 2010. Thyroid function tests during first: Trimester of pregnancy: A review of litrature. Pak. J. Biol. Sci., 13: 664-673.

Mansourian, A.R., A.R. Ahmadi, A. Saifi and S. Bakhshandehnosrat, 2010. The children reference range of thyroid hormones in Northern Iran. Pak. J. Biol. Sci., 13: 862-865.
CrossRefDirect Link

Mansourian, A.R., A.R. Ahmadi, H.R. Mansourian, A. Sifi, A. Marjani and E. Ghaemi, 2010. Maternal thyroid stimulating hormone level during the first trimester of pregnancy at South East of Caspian sea in Iran. J. Clin. Diagnostic Res., 4: 2472-2477.

Mansourian, A.R., E.O. Ghaemi, A. Ahmadi, A. Marjani, A. Saifi and S. Bakhshandehnosrat, 2008. Serum lipid level alteration in sub clinical hypothyroid patients in Gorgan (South East Caspian Sea). J. Chinese Clin. Med., 3: 206-210.
Direct Link

Mansourian, A.R., E.O. Ghaemi, A.R. Ahmadi, A. Saifi, A.V. Moradi and S. Bakhshandeh-Nosrat, 2007. A survey of urinary iodine concentration in South-East of Caspian Sea in Northern, Iran. Pak. J. Biol. Sci., 10: 2166-2171.
CrossRefPubMedDirect Link

Marino, M. and R.T. McCluskey, 2000. Role of thyroglobulin endocytic pathways in the control of thyroid hormone release. Am. J. Physiol. Cell Physiol., 279: 1295-1306.
Direct Link

Marino, M., G. Zheng, L. Chivato, A. Pinchera, D. Brown, D. Andrews and R.T. McCluskey, 2000. Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release. J. Biol. Chem., 275: 7125-7137.
PubMed

Marriq, C., P.J. Lejeune, N. Venot and L. Vinet, 1991. Hormone formation in the isolated fragment 1-171 of human thyroglobulin involves the couple tyrosine 5 and tyrosine 130. Mol. Cell Endocrinol., 81: 155-164.
PubMed

Mazzaferri, E.L., R.J. Robbins, C.A. Spencer, L.E. Braverman and F. Pacini et al., 2003. A concensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinomas. J. Clin. Endocrinol. Metab., 88: 1433-1441.
PubMed

McDougall, I.R. and R.J. Weigel, 2001. Recombinant human thyrotropin in the management of thyroid cancer. Curr. Opin. Oncol., 13: 39-43.
PubMed

Medeiros-Neto, G. and J.B. Stanbury, 1994. The Iodotyrosine Deiodinase Defect. In: Inherited Disorders of the Thyroid System, Medeiros-Neto, G. and J.B. Stanbury (Eds.). CRC Press, Boca Raton.

Medeiros-Neto, G., P.S. Kim, S.E. Yoo, J. Vono and H.M. Targovnik et al., 1996. Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones. J. Clin. Invest., 98: 2838-2844.
CrossRef

Mendive, F.M., C.M. Rivolta, C.M. Moya, G. Vassart and H.M. Targovnik, 2001. Genomic organization of the human thyroglobulin gene: The complete intron-exon structure. Eur. J. Endocrinol., 145: 485-496.
CrossRef

Mercken, L., M.J. Simons, S. Swillens, M. Massaer and G. Vassart, 1985. Primary structure of bovine thyroglobulin deduced from the sequence of its 8,431-base complementary DNA. Nat., 316: 647-651.
CrossRef

Montuori, N., F. Pacifico, S. Mellone, D. Liguoro and B. Di-Jeso et al., 2000. The rat asialoglycoprotein receptor binds the amino-terminal domain of thyroglobulin. Biochem. Biophys. Res. Commun., 268: 42-46.
PubMed

Muresan, Z. and P. Arvan, 1997. Thyroglobulin transport along the secretory pathway. J. Biol. Chem., 272: 26095-26102.
PubMed

Muresan, Z. and P. Arvan, 1998. Enhanced binding to the molecular chaperone BiP slows thyroglobulin export from the endoplasmic reticulum. Mol. Endocrinol., 12: 458-467.
Direct Link

Nakamura, Y., S. Ohtaki, R. Makino, T. Tanaka and Y. Ishimura, 1989. Superoxide anion is the initial product in the hydrogen peroxide formation catalyzed by NADPH oxidase in porcine thyroid plasma membrane. J. Biol. Chem., 264: 4759-4761.
Direct Link

Neve, P., C. Willems and J.E. Dumont, 1970. Involvement of the microtubule-microfilament system in thyroid secretion. Exp. Cell Res., 63: 457-460.
PubMed

Niepomniszcze, H., L.J. De Groot and G.A. Hagen, 1972. Abnormal thyroid peroxidase causing iodide organification defect. J. Clin. Endocrinol. Metab., 34: 607-607.
CrossRef

Ofverholm, T. and L.E. Ericson, 1984. Intralumenal iodination of thyroglobulin. Endocrinology, 114: 827-835.
PubMedDirect Link

Ohtaki, S., H. Nakagawa, S. Kimura and I. Yamazaki, 1981. Analyses of catalytic intermediates of hog thyroid peroxidase during its iodinating reaction. J. Biol. Chem., 256: 805-810.
Direct Link

Ohtaki, S., S. Moriya, H. Suzuki and Y. Horiuchi, 1967. Nonhormonal iodine escape from the normal and abnormal thyroid gland. J. Clin. Endocrinol. Metab., 27: 728-740.
CrossRef

Ohyama, Y., T. Hosoya, T. Kameya, N. Suzukl and S. Nakamura et al., 1994. Congenital euthyroid goitre with impaired thyroglobulin transport. Clin. Endocrinol., 41: 129-135.
CrossRef

Pharoah, P.O.D. and K.J. Connolly, 1987. A controlled trial of iodinated oil for the prevention of endemic cretinism: A long-term follow-up. Int. J. Epidemiol., 16: 68-73.
CrossRefDirect Link

Pierce, L.R., C. Zurzolo, G. Salvatore, and H. Edelhoch, 1985. Coated vesicles from the thyroid gland: Isolation, characterization and a search for a possible role in thyroglobulin transport. J. Endocrinol. Invest., 8: 303-312.
PubMed

Portmann, L., N. Hamada, G. Heinrich and L.J. De-Groot, 1985. Antithyroid peroxidase antibody in patients with autoimmune thyroid disease: Possible identity with antimicrosomal antibody. J. Clin. Endocrinol. Metab., 61: 1001-1003.
Direct Link

Robbins, J., J. Wolff and J.E. Rall, 1959. Iodoproteins in normal and abnormal human thyroid tissue and in normal sheep thyroid. Endocrinology, 64: 37-52.
PubMed

Robbins, R.J., R.M. Tuttle, R.N. Sharaf, S.M. Larson and H.K. Robbins et al., 2001. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinomas. J. Clin. Endocr. Metab., 86: 619-625.
Direct Link

Rosenberg, I.N. and A. Goswami, 1979. Purification and characterization of a flavoprotein from bovine thyroid with iodotyrosine deiodinase activity. J. Biol. Chem., 254: 12318-12385.
PubMed

Rousset, B. and R. Mornex, 1991. The thyroid hormone secretary pathway-Current dogmas and alternative hypotheses. Mol. Cell Endocrinol., 78: 89-93.
PubMed

Ruf, J., B. Czarnocka, C. De Micco, C. Dutoit, M. Ferrand and P. Carayon, 1987. Thyroid peroxidase is the organ-specific `microsomal` autoantigen involved in thyroid autoimmunity. Acta Endocrinol. Suppl., 281: 49-56.
CrossRef

Schlumberger, M., M. Ricard and F. Pacini, 2000. Clinical use of recombinant human TSH in thyroid cancer patients. Eur. J. Endocrinol., 143: 557-563.
PubMed

Schneider, A.B., K. Ikekubo and K. Kuma, 1983. Iodine content of serum thyroglobulin in normal individuals and patients with thyroid tumors. J. Clin. Endocrinol. Metab., 57: 1251-1256.
CrossRef

Selmi, S. and B. Rousset, 1988. Identification of two subpopulations of thyroid lysosomes: Relation to the thyroglobulin proteolytic pathway. Biochem. J., 253: 523-532.
Direct Link

Seto, P., H. Hirayu, R.P. Magnusson, J. Gestautas, L. Portmann, L.J. De Groot and B. Rapoport, 1987. Isolation of a complementary DNA clone for thyroid microsomal antigen. Homology with the gene for thyroid peroxidase. J. Clin. Invest., 80: 1205-1208.
CrossRef

Shahmohammdi, F., A.R. Mansourian and H.R. Mansourian, 2008. Serum thyroid hormone level in women with nausea and vomiting in early pregnancy. J. Med. Sci., 8: 507-510.
CrossRefDirect Link

Spencer, C.A., 2000. Serum thyroglobulin measurements: Clinical utility and technical limitations in the management of patients with differentiated thyroid carcinomas. Endocr. Pract., 6: 481-484.
PubMed

Spiro, M.J. and K.M. Gorski, 1986. Studies on the posttranslational migration and processing of thyroglobulin: Use of inhabitors and evaluation of the role of phosphorylation. Endocrinology, 119: 1146-1158.
PubMed

Spiro, M.J., 1977. Presence of a glucuronic acid-containing carbohydrate unit in human thyroglobulin. J. Biol. Chem., 252: 5424-5430.
PubMed

Targovnik, H.M., J. Vono, A.E. Billerbeck, G.E. Cerrone and V. Varela et al., 1995. A 138-nucleotide deletion in the thyroglobulin ribonucleic acid messenger in a congenital goiter with defective thyroglobulin synthesis. J. Clin. Endocrinol. Metab., 80: 3356-3360.
PubMed

Tietze, F., L.D. Kohn, A.D. Kohn, I. Bernardini and H.C. Andersson et al., 1989. Carrier-mediated transport of monoiodotyrosine out of thyroid cell lysosomes. J. Biol. Chem., 264: 4762-4765.
PubMed

Tonglet, R., P. Bourdoux, T. Minga and A.M. Ermans, 1992. Efficacy of low oral doses of iodized oil in the control of iodine deficiency in Zaire. N. Engl. J. Med., 326: 236-241.
Direct Link

Toyoda, N., M. Nishikawa, Y. Mori, M. Yoshimura and H. Masaki et al., 1992. Identification of a 27-kilodalton protein with the properties of type I Iodothyronine 5`-deiodinase in human thyroid gland. J. Clin. Endocrinol. Metab., 74: 533-538.
PubMed

Virion, A., F. Courtin, D. Deme, J.L. Michot, J. Kaniewski and J. Pommier, 1985. Spectral characteristics and catalytic properties of thyroid peroxidase-H2O2 compounds in the iodination and coupling reactions. Arch. Biochem. Biophys., 242: 41-47.
CrossRef

Virion, A., J. Pommier, D. Deme and J. Nunez, 1981. Kinetics of thyroglobulin iodination and thyroid hormone synthesis catalyzed by peroxidase: The role of H2O2. Eur. J. Biochem., 117: 103-109.
CrossRef

Wartofsky, L. and rhTSH-Stimulated Thyroglobulin Study Group, 2002. Management of low-risk well-differentiated thyroid cancer based only on thyroglobulin measurement after recombinant human thyrotropin. Thyroid, 12: 583-590.
PubMed

Wolff, J. and I.L. Chaikoff, 1948. Plasma inorganic iodide as a homeostatic regulator of thyroid function. J. Biol. Chem., 174: 555-564.
PubMed

Wollman, S.H. and R. Ekholm, 1981. Site of iodination in hyperplastic thyroid glands deduced from autoradiographs. Endocrinology, 108: 2082-2085.
PubMed

Yamamoto, K., T. Tsuji, O. Tarutani and T. Osawa, 1984. Structural changes of carbohydrate chains of human thyroglobulin accompanying malignant transformations of thyroid glands. Eur. J. Biochem., 143: 133-144.
CrossRef