Iodine, thyroid hormone synthesis

Taurog A (2000) Thyroid hormone synthesis Thyroid iodine metabolism. In Braverman LE, Utiger RD (eds) Werner and Ingbar The thyroid. Lippincott Williams Wilkins, Philadelphia, PA, pp 61-85... 

The answer is c. (Katzung, pp 651-652.) Propylthiouracil is a thioamide that interferes with the production of thyroid hormone. Its primary action is prevention of thyroid hormone synthesis by blocking thyroid peroxidase catalysis leading to interference with iodine organification. 

The concentration of Li+ in the thyroid is three to four times that in serum [179]. It is thought that Li+ may be concentrated in the thyroid gland by a mechanism similar to the incorporation of iodide, I-, resulting in competition between Li+ and I the levels of intracellular 1 decrease when those of Li+ increase, and vice versa [182]. Li+ inhibits both the ability of the gland to accumulate 1 and the release of iodine from the gland. In vitro, Li+ has no effect on thyroid peroxidase, the enzyme that catalyzes the incorporation of I" into tyrosyl residues leading to thyroidal hormone synthesis, but does increase the activity of iodotyrosine-deio-dinase, which catalyzes the reductive deiodination of iodotyrosyls, thus maintaining the levels of intracellular I [182]. The increase in iodoty-rosine-deiodinase activity is probably a response to the Li+-induced decrease in the concentration of thyroidal I". Li+ has no effect on the conversion of thyroxine to triiodothyronine. The overall effect of this competition between Li+ and 1 is, therefore, reduced levels of thyroid hormone in the presence of Li+. 

Drugs used for hyperthyroidism can be classified as drugs that suppress thyroid hormone synthesis in the anterior lobe of the hypophysis, and they consist of diiodotyrosine and iodine, as well as drugs that suppress thyroid hormone synthesis in thyroid glands (propylthiouracil, methylthiouracil, methimazole, and carbimazole). 

Thioamides are reducing agents. They inhibit thyroid hormone synthesis by inhibiting the peroxidase enzymatic system, which catalyzes oxidation of iodide ions and iodine that are consumed in food, which is necessary for iodination of tyrosine derivatives. Thus they reduce the concentration of free iodine necessary to react with tyrosine derivatives, and they can also block oxidative addition reactions of mono- and diiodtyrosines, which form L-thyroxine and L-triiodothyronin. 

A normal rate of thyroid hormone synthesis depends on an adequate dietary intake of iodine. Iodine is naturally present in water and soil, although some soils contain very low amounts. As a result, seafood is a more reliable source of iodine than crop plants. Approximately 1.6 billion people in more than 100 countries live in areas where natural sources of dietary iodine intake are marginal or insufficient. A minimum of 60 j.g of elemental iodine is required each day for thyroid hormone synthesis, and at least 100 j.g/day is required to eliminate thyroid follicular cell hyperplasia and thyroid enlargement (i.e., iodine deficiency goiter). 

The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH. These mechanisms are primarily related to the level of iodine in the blood. Large doses of iodine inhibit iodide organification (Wolff-Chaikoff block, see Figure 38-1). In certain disease states (eg, Hashimoto s thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism. Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter). 

PURPOSE AND RATIONALE Propyl-thiouracil (PTU) and a wide spectrum of drugs may inhibit thyroid hormone synthesis. Some of these drugs can be used for treatment of thyrotoxicosis. As consequence of thyroid peroxidase inhibition, the iodine uptake and content of the thyroid is decreased. This phenomenon is dose-dependent and may occur at lower doses than those increasing thyroid weight in rats (McGinty and Bywater 1945). The historical parameter of iodine content was replaced by measuring uptake and release of radio-iodine (131-1). 

Thyroid hormone synthesis requires oxidation of dietary iodine, followed by iodination of tyrosine to mono- and diiodotyrosine coupling of iodotyrosines leads to formation of the active molecules, tetraiodo-tyrosine, (T or L-th3rroxine) and triiodotyrosine (Tj or L-thyronine). 

Conversion of Inorganic Iodine into Organic Iodine, and Thyroid Hormone Synthesis... 

The third step in thyroid hormone synthesis is cleavage of the aromatic R group from one of the iodinated tyrosines in the dimer. As a result, one of the iodotyros-... 

The second step in thyroid hormone synthesis is the covalent bridging of two different residues of iodinated tyrosine. A dimer is formed, reminiscent of the dimers of cysteine in proteins (the cysteine dimer is called cystine). Only a small fraction of the iodinated tyrosines is bridged in this way. More specifically, only four of the iodinated tyrosines, located at positions 5,2555,2569, and 2748, participate in the reaction. The numbers refer to the amino acid, cormting from the amino terminus of the protein. Thyroglobulin has 2748 amino acids. The first and second steps are catalyzed by thyroperoxidase, a heme protein. It requires hydrogen peroxide for activity. To summarize, thyroperoxidase catalyzes the attachment of iodine atoms to residues of tyrosine as well as the subsequent cross-linking of the iodinated tyrosine residues. 

FIGURE 10.21 Iodine uptake and thyroid hormone synthesis by the thyroid gland. Thy-roglobulin is broken down to yield T4 and T3 as well as iodotyrosine byproducts. These byproducts are further broken down in the thyroid to yield iodide. 

In hyperthyroidism, inhibits synthesis of thyroid hormone. Diverts iodine from thyroid hormone synthesis. 

The synthesis of T3, T4, DIT, and MIT in Tg molecules occurs mainly at the follicular ceU-colloid interface but also within the colloid. Tg is present m highest concentrations within the colloid, where it is stored. The follicular cells engulf colloid globules by endocytosis these globules then merge with lysosomes in the foUicular cell. Lysosomal proteases break the peptide bonds between iodinated residues and Tg, and T4, T3, DIT, and MIT are released into the cytoplasm of the follicular cell. T4 and T3 diffuse into the systemic circulation after their liberation from Tg. DIT and MIT are deiodinated by an intracellular microsomal iodoty-rosine dehalogenase. The freed iodide is then reused for thyroid hormone synthesis. 

The answer is c. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121-138. Wilson, pp 287-320.) Certain amino acids and lipids are dietary necessities because humans cannot synthesize them. The energy usually obtained from carbohydrates can be obtained from lipids and the conversion of some amino acids to intermediates of the citric acid cycle. These alternative substrates can thus provide fuel for oxidation and energy plus reducing equivalents for biosynthesis. Iodine is important for thyroid hormone synthesis, while calcium is essential for muscle contraction and bone metabolism. 

Iodine deficiency causes an increase in the ratio of MIT to DIT in thyroglobufin and leads to a relative increase in the production of T3. Because T3 is more potent than T4, the increase in T3 production in iodine-depleted areas may be beneficial. The thionamide drugs used to treat hyperthyroidism inhibit thyroid peroxidase and thus block thyroid hormone synthesis. 

Thyroid-stimulating hormone (TSH)—A polypeptide hormone secreted by the anterior pituitary gland that stimulates iodine uptake and thyroid hormone synthesis. 

The steps in thyroid hormone synthesis and the antithyroid agents effects upon them are summarized in Table VII-2-2. The clinical uses and their potential complications are presented in greater detail for the thioamides (propylthiouracil and methimazole) and iodine. 

Hypothyroidism (thyroid hormone deficiency) may result from autoimmune disease (Hashimoto s disease) or from deficient synthesis of TSH or TRH (thyroid-stimulating hormone-releasing factor). Because adequate ingestion of iodine is a prerequisite for thyroid hormone synthesis, iodine deficiency also causes hypothyroidism. In children, thyroid hormone deficiency (called cretinism) causes depressed growth and mental retardation. Severe hypothyroidism in adults (myxedema) results in symptoms such as edema (abnormal fluid accumulation) and goiter. Hypothyroidism is usually treated with hormone replacement therapy. 

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