Thyroid biosynthesis

Certain phytoestrogens have also been suggested to inhibit enzymes involved in estrogen biosynthesis and metabolism, as well as thyroid biosynthesis. Preliminary studies suggest they inhibit protein kinases and topoisomerases, as well as influence the cell cycle and subsequent proliferation, differentiation and apoptotic pathways. Interest in phytoestrogens, such as isoflavones, has increased since they are reported to exhibit some nonhormonal effects, such as antioxidation. 

W5. Wellby, M. L., Defective thyroid biosynthesis A cause of mental and physical retardation. Aust. J. Ment. Retard. 1, 191-195 (1971). 

A deiodinase removes 1 from the inactive mono-and diiodothyronine molecules in the thyroid. This mechanism provides a substantial amount of the 1 used in T3 and T4 biosynthesis. A peripheral deiodinase in target tissues such as pituitary, kidney, and fiver selectively removes T from tfie 5 position of T4 to make T3 (see Figure 42-2), wfiicfi is a mucfi more active molecule. In this sense, T4 can be thought of as a prohormone, though it does have some intrinsic activity. 

Another important example of catalytic oxidation of inorganic compounds by peroxidases is the catalysis of iodide oxidation by TPO. TPO is involved in the biosynthesis of thyroid hormone and catalyzes the reactions of iodination and coupling in the thyroid gland. Magnusson et al. [215] considered two possible pathways of iodination the formation of enzyme-bound hypoiodite and the formation of free hypoiodide (Reactions (17) and (18)) ... 

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. 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

BIOSYNTHESIS, STORAGE, SECRETION, AND METABOLISM OF THYROID HORMONES... 

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. 

The thyroid and parathyroid glands are two important endocrine organs that are heavily committed to the biosynthesis of hormones as chemical messengers. The thyroid gland, which surrounds the larynx, has an enormous variety of metabolic functions. It is itself regulated by thyroliberin, which in turn regulates production of thyrotropin (thyroid... 

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

The human body contains lactoperoxidase, a product of exocrine secretion into milk, saliva, tears, etc., and peroxidases with specialized functions in saliva, the thyroid, eosinophils,219 and neutrophils.220 The functions are largely protective but the enzymes also participate in biosynthesis. Mammalian peroxidases have heme covalently linked to the proteins, as indicated in Fig. 16-12 220 222a... 

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. 

The toxicological hazard of perchlorate salts may depend on the cation in the compound. In general, the salts should be considered as skin irritants and treated as such. Perchlorate ion, C104, may compete physiologically with iodide ion, U. This can occur in the uptake of iodide by the thyroid, leading to the biosynthesis of thyroid hormones. As a consequence, perchlorate can cause symptoms of iodine deficiency. 

In this chapter we will first briefly describe the major parameters controlling the level of thyroid hormone production and its concentration by the target cell (see Ref. 6), i.e., biosynthesis and output from the thyroid gland, transport in the blood, conversion of the prohormone thyroxine (T4), to the active form, 3,5,3 -triiodo-... 

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],... 

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