Thyroid hormone iodothyronines

PTU and MMI block thyroid hormone synthesis by inhibiting the peroxidase enzyme system of the thyroid gland, thus preventing oxidation of trapped iodide and subsequent incorporation into iodotyrosines and ultimately iodothyronine ( organification ) and by inhibiting coupling of MIT and DIT to form T4 and T3. PTU (but not MMI) also inhibits the peripheral conversion of T4 to T3. 

Two amino acids, tyrosine and arginine are of particular importance as precursors of signalling molecules. As outlined in Figure 4.3, tyrosine is the amino acid precursor of thyroid hormones tri-iodothyronine (T3) and tetra-iodothyronine (T4) and also of catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). 

Three hormones are secreted by the thyroid thyroxine (T4) and tri-iodothyronine (T3) are usually referred to as the thyroid hormones and calcitonin, a peptide, which under certain circumstances, affects calcium mobilization and is secreted from specialized so-called C cells. Only T3 and T4 will be discussed further at this point. 

Figure 7.4 The effect of bile acids on energy expenditure. Circulating bile acids bind to the G-protein-coupled receptor, TGR5 that stimulates increased cAMP-PKA activation and increased expression of type-2 iodothyronine deiodinase (D2). This response is sensitised by a high-fat diet. D2 converts thyroxine (T4) to active 3,5,3 -tri-iodothyronine (T3). T3 stimulates thyroid hormone receptor binding to target genes. This leads to altered expression of genes associated with energy balance, and increased energy expenditure.

Walpita CN, Crawford AD, Janssens EDR, Van der Geyten S, Darras VM (2009) Type 2 iodothyronine deiodinase Is essential for thyroid hormone-dependent embryonic development and pigmentation in zebrafish. Endocrinology 150 530-539... 

Walpita CN, Van der Geyten S, Rurangwa E, Darras VM (2007) The effect of 3,5,3 -triiodothyronine supplementation on zebrafish (Danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors. Gen Comp Endocrinol 152 206-214... 

The thyroid hormone thyroxine (tetraiodo-thyronine, T4) and its active form triiodothyronine (T3) are derived from the amino acid tyrosine. The iodine atoms at positions 3 and 5 of the two phenol rings are characteristic of them. Post-translational synthesis of thyroxine takes place in the thyroid gland from tyrosine residues of the protein thyro-globulin, from which it is proteolytically cleaved before being released, iodothyronines are the only organic molecules in the animal organism that contain iodine. They increase the basal metabolic rate, partly by regulating mitochondrial ATP synthesis, in addition, they promote embryonic development. 

The final step in thyroid hormone synthesis is the coupling of two iodotyrosines within a single peptide chain of Tg to form the iodothyronine T4 or T3. Both the coupling of two DITs to form T4 and the coupling of a MIT with a DIT to form T3 are catalyzed by the enzyme TPO. 

Three types of iodothyronine deiodinase remove iodine atoms from thyroxine to form the active thyroid hormone triiodothyronine and also to inactivate the hormone by removing additional iodine531 541-546 (see also Chapter 25). In this case the - CH2- Se- may attach the iodine atom, removing it as I+ to form -CH2-Se-I. The process could be assisted by the phenolic -OH group if it were first tautomerized (Eq. 15-60). 

The transplacental passage of maternal iodothyronines is quantitatively modest, although it might be sufficient to ensure adequate fetal development. Maternal thyroid hormone secretion is markedly increased during pregnancy (by 25-50%) thyroid therapy should therefore be carefully adjusted during pregnancy (58). 

Hypothyroidism developed within 2 weeks of rifampicin therapy in these patients and resolved when it was withdrawn. Rifampicin increases thyroxine clearance, possibly by enhancing hepatic thyroxine metabolism and the biliary excretion of iodothyronine conjugates. In healthy volunteers rifampicin reduces circulating thyroid hormone concentrations without affecting thyrotropin, suggesting that rifampicin directly reduces thyroid hormone concentrations. 

Thyroid hormones are necessary for the development and function of cells throughout the body. The thyroid hormones thyroxine and tri-iodothyronine (Figure 7.7) are not peptides, but are actually simple derivatives of tyrosine. However, they are believed to be derived by degradation of a larger protein molecule. One... 

E.V. Ivleva (1989a) found that, during the winter, Black Sea horse-mackerel displayed increased thyroid activity. This is directly related to the intensity of energy metabolism. Other workers found enhanced growth of the follicular cells of the thyroid gland of brown trout and brook trout during periods of low temperature (Woodhead and Woodhead, 1965a,b Drury and Eales, 1968), and increased thyroxine levels in the blood plasma (Eales et al, 1982). On the other hand, Leatherland (1994) has demonstrated a close positive correlation between water temperature and the concentrations of both forms of thyroid hormone (thyroxine and tri-iodothyronine) in the plasma of brown bullhead. 

Fig. 1. Major thyroid hormones (3,5,3 ,5 -tetraiodothyronine or thyroxine, T4) and (3,5,3 triiodothy-ronine, T,) and other important iodothyronines (3,3,5 -triiodothyronine or reverse-T, r-T and 3,3 -diiodothyronine 3,3 -T2). T4 and T, are active, r-Tj and 3,3 -T, are inactive. The acetic derivatives of T4 (TETRAC) and T, (TRIAC) are produced by oxidative decarboxylation of the alanine side-chain and have thyromimetic activities.

In rats equilibrated with radioiodine-labelled T4 or T3 roughly half of the radioactivity appears as I- in the urine and the other half as free iodothyronines in the feces [12]. Treatment of the rats with 6-propyl-2-thiouracil (PTU) results in a marked decrease in urinary radioactivity and a reciprocal increase in fecal clearance [12]. Also, in humans, PTU has been shown to inhibit peripheral iodothyronine deiodination besides its well-known effect on thyroid hormone biosynthesis [13]. Compared with the rat, deiodination is an even more important pathway for the clearance of thyroid hormone in man as evidenced by the greater proportion undergoing urinary clearance [2]. Furthermore, estimation of iodothyronine turnover kinetics in humans has demonstrated that a major fraction of T4 disposal is accounted for by plasma production rates of T3 and rT3 [2,3],... 

Recent investigations of the metabolism of iodothyronines in different tissues especially of the rat have led to the recognition of at least three different iodothyron-ine-deiodinating enzymes [5-8] (Table I). These deiodinases have in common that they are located in the membrane fractions of the tissues and that they are stimulated by sulfhydryl (SH) compounds, especially dithiols [5-8]. However, important differences exist between the specificities and catalytic mechanisms of these enzymes, their tissue distribution, sensitivity to PTU and other inhibitors, and regulation by thyroid hormone [5-8]. The characteristics of the different deiodinases will be discussed in more detail in Sections 2 and 3. 

The concept that plasma membrane transport plays a key role in the regulation of intracellular thyroid hormone levels is supported by studies with a monoclonal antibody against an antigen exposed on rat liver cells [107], This antibody inhibited the uptake of different iodothyronines by rat hepatocytes under initial rate conditions as well as the metabolism of these compounds during prolonged incubations [107]. Uptake and metabolism of T4, T3 and rT3 were affected to the same extent, suggesting that a single system operates in the transport of different iodothyronines, which is opposite to the view advanced above. However, it is not excluded that the antibody interacts with a component of the plasma membrane and thereby affects multiple transport systems. 

Iodothyronine deiodinases have been grouped into three classes—Types I, II and III— based on such parameters as substrate specificities, kinetics and sites of deiodination. The conversion of T4 to the more active T3 demonstrates the importance of deiodinases in thyroid function. The further deiodination of T3 to inactive iodothyronines provides a further mechanism for attenuating the action of the thyroid hormones (see below). 

Selenium This metal is an essential trace element that functions as a component of enzymes involved in antioxidant protection and thyroid hormone metabolism. The existence of a number of selenoproteins has been demonstrated. In several intra- and extracellular glutathione peroxidases and iodothyronine... 

MOA Thioamides inhibit the synthesis of thyroid hormones by inhibiting thyroid peroxidase-catalyzed reactions to block iodine organification. Thioamides also block coupling of mono-iodothyronine and diiodothyronine. PTU also inhibits the peripheral conversion of T to Tj. 

Thyroglobulin. a glycoprotein, is composed of several peptide chains it also contains 0.5 to 1% iodine and 8 (o 10% carbohydrate in (he form of two types of poly.saccharide. The formation of thyroglobulin is regulated by TSH. Thyroglobulin has no hormonal properties. I( must be hydrolyzed to release the hormonal iodothyronines thyroxine and liothy-lonine (see Thyroid Hormones" in Chapter 19). 

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