Thyroid hormones biosynthesis

Iodide acutely blocks thyroid hormone release, inhibits thyroid hormone biosynthesis by interfering with intrathyroidal iodide use, and decreases the size and vascularity of the gland. 

Diets rich in millet have been associated with endemic goiter in parts of West Africa where millet is a staple. The damage has been attributed to vitexin, a C-glycosyl flavone, that in rats has antithyroid activity and that in vitro inhibits thyroid peroxidase and the free radical iodination step in thyroid hormone biosynthesis. Isoflavones have produced similar antithyroid effects in rats, but clinical studies in adults have not. " However, this remains a possible concern in infants fed soya-based milk-replacers, especially if iodine supply is compromised. 

Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown... 

The primary steps in thyroid hormone biosynthesis are shown schematically in Figure 31-2. Thyroid follicle cells take up and concentrate iodide from the bloodstream—this is significant because there must be a sufficient amount of iodine in the diet to provide what is needed for thyroid hormone production.55 Thyroid cells also manufacture a protein known as thy-... 

FIGURE 31-2 Thyroid hormone biosynthesis. Iodide is taken into the follicle cell, where it is converted by thyroid peroxidase to an oxidized form of iodine (Ip). h is transported to the follicle lumen, where it is bonded to tyrosine residues of the thyroglobulin [TGB] molecule. Iodinated TGB is incorporated back into the cell, where it undergoes lysis to yield the thyroid hormones T3 and T4. See text for further discussion. 

Iodide. Relatively large dosages of iodide (exceeding 6 mg/d) cause a rapid and dramatic decrease in thyroid function.35 In sufficient amounts, iodide inhibits virtually all the steps involved in thyroid hormone biosynthesis. For instance, high iodide levels limit the uptake of iodide into thyroid follicle cells, inhibit the formation of T4 and T3, and decrease the secretion of the completed hormones from the thyroid cell. 

Fig. 2. Different parameters contributing to the hormone concentration in blood and in the target cells 1) hypothalamic (TRH)-pituitary (TSH) control of 2) thyroid hormone biosynthesis by the thyroid gland, 3) enterohepatic circulation of T4 and T3 and 4) conversion of T4 to either T, or r-T3 by the target cells.

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],... 

Figure 2.6 Dorzolamide 16, a topically active carbonic anhydrase inhibitor, resulted from a structure-based ligand design it is used for the treatment of glaucoma. Sulfaguanidine 17 inhibits thyroid hormone biosynthesis. A phenylog of sulfanilamide 11 (Figure 2.4), dapsone 18, is used for the treatment of leprosy.

Many structural or functional abnormalities of the thyroid gland can lead to thyroid hormone deficiency (Box 52-2). Primary hypothyroidism is frequently caused by diseases or treatments that directly destroy thyroid tissue or interfere with thyroid hormone biosynthesis. Secondary hypothyroidism occurs as a result of pituitary or hypothalamic disease and/or disorders. 

Primary goitrous hypothyroidism results when the synthesis of T4 and T3 is impaired, either because of some extrinsic factor or because of an intrinsic, inherited defect in thyroid hormone biosynthesis. As a result, the positive feedback loop causes compensatory thyroid enlargement (goiter) through the hypersecretion of TRH and TSH. Primary nongoitrous hypothyroidism is characterized by loss or atrophy of thyroid tissue, resulting in decreased production of thyroid hormones despite maximum stimulation by TSH. Hashimotos thyroiditis is the most frequent cause of primary hypothyroidism in developed countries where iodine intake is sufficient. Worldwide, iodine deficiency is the most common cause of goitrous hypothyroidism. The... 

Thyroid hormone biosynthesis (Figure 45-2) involves the concentrative uptake of iodide into thyroid cells where it is converted into iodine by thyroid peroxidase in the colloid space of the folhcular lumen. Iodine is incorporated into tyrosine residues of thyroglobuhn contained within the colloid space at the basal surface of the thyroid follicular cell. Tyrosine residues are iodinated... 

TSH binds a G protein-coupled receptor to activate adenylate cyclase and trigger a signaling cascade leading to thyroid hormone biosynthesis. 

FIGURE 56-2 Major pathways of thyroid hormone biosynthesis and release. 

A diet lacking in iodine can have adverse effects on health, since iodine is essential for thyroid hormone biosynthesis. Many external and internal factors are known to influence the transport of iodine to thyroid follicular cells and thyroid hormone biosynthesis, metabohsm, and actions in target cells. Soy isoflavones are among the nutritional factors that may exert an effect on these processes. 

Figure 38.2 Possible sites of inhibitory actions of soy isoflavones on iodine utilization and thyroid hormone biosynthesis and actions. Soy isoflavonoids, genistein and daidzein, inhibit oxidation of iodide by thyroid peroxidase at the apical membrane of thyroid follicular cells, followed by iodination of tyrosine residues in thyroglobulin and their coupling in colloid. In addition, they may affect deiodination of iodothyronines and interfere with thyroid hormone binding to transthyretin. Full arrows indicate the sites of inhibition. So far, only few reports concern the effect of thyroid hormone actions in target cells.

The available data from in vivo, as well as from in vitro, experiments clearly demonstrate that soy isoflavones act as inhibitors of TPO and thus may influence iodine incorporation in thyroid hormone biosynthesis. On the other hand, most of the cfinical trials, including our own, have shown only modest and transitory effects of soy isoflavones on circulating thyroid hormone levels. However, they may be important in the case of insufficient iodine supply. Besides thyroid hormone biosynthesis, soy isoflavones may influence other events involved in thyroid function, such as iodine transport, thyroid hormone deiodination, and signaling pathways. So far, the data available on these topics is scarce and more experiments addressing these issues are needed. 

Clinical trials, including ours, have been undertaken to ascertain whether soy food consumption can influence thyroid function, especially actual thyroid hormone biosynthesis and actual thyroid hormone levels. 

About half of the blood iodine is associated with the red cells the remaining is in the serum. The serum contains 1 pg of inorganic iodides per 100 ml. The inorganic iodide in the general circulation is picked up mainly by two organs— the kidney, which excretes the iodide, and the thyroid, which uses it for thyroid hormone biosynthesis. 

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