Triodothyronine (T3) and Tetraiodothyronine (T4) Hormones

The below mentioned article provides an overview on Triodothyronine (T₃) and Tetraiodothyronine (T₄) Hormones. After reading this article you will learn about: 1. Meaning of T₃ and T₄ Hormones 2. Biosynthesis of T₃ and T₄ Hormones 3. Transport 4. Catabolism 5. Control of Secretion.

Meaning of T₃ and T₄ Hormones:

T₃ and T₄ are popularly known as triiodot­hyronine and tetraiodothyronine or thyrox­ine respectively. These hormones are se­creted from principal follicular cells of thy­roid gland. Kendall (1918) isolated the ac­tive component of the thyroid that he named thyroxine. In 1952, triiodothyronine was found to be more active than thyroxine. These hormones are iodo amino acid hormones.

Biosynthesis of T₃ and T₄ Hormones:

T₃ and T₄ are iodinated derivatives of amino acid tyrosine. These hormones are unique in that they are complexed through covalent bonds to iodine.

Biosynthesis of thyroid hormones are describe below:

1. Trapping of Iodide:

Thyroid follicular cells collect inorganic iodide (I^–) from blood against steep electrochemical gra­dients with the help of carrier protein. (Sodium iodide symporter) located in the basal plasma membrane in association with Na⁺-K⁺-ATPase. This is known as “iodite pump”.

The carrier protein carri­ers iodide (l^–) while ATPase causes (i) breakdown of ATP into ADP and Pi to derive energy for iodine transport and (ii) a simultaneous exchange of Na⁺ and K⁺ ions between the cells and extracellular fluid. The concentration for iodide achieved by the normal thyroid is 20:1, or more, over the blood plasma. Within 1 5 minutes, af­ter administration radioactivity in the thy­roid is present in organic compounds.

2. Oxidation of Iodide:

Next inorganic iodites (I^–) are oxidized into “active io­dine or l⁺/IO^– or iodinium ions” through removal of electrons within the follicu­lar cells in presence of enzyme, tetrameric-heme-enzyme called thyroid peroxidase. This enzyme uses H₂O₂ as a co-substrate. This reaction is chiefly occurred in the microvilli of the follicu­lar cells.

3. lodination of Tyrosine:

The follicular cells synthesis a glycoprotein, thyroglobulin (mol. wt. 669 kdt) which contains 115 tyrosine residues. Thyroglobulin passes into the colloid by the process of exocytosis. In inorganic iodide that accumulates in the follicular epithelium is oxidized to l₂ (elemental iodine) or IO^–. At the follicular cell membrane colloid interface, thyroperoxidase utilizes the active iodides for iodination of some of the tyrosine residues of thyroglobulin mol­ecules of colloid.

MIT or 3-monoiodotyrosine is produced when one iodine replaces a hydrogen at C₃ of the phenyl ring of a tyrosine and DIT or 3’5-diiodotyrosine is produced if two iodine’s replaces two hydrogen’s at C₃ and C₅ of phenyl ring of tyrosine. Most of the iodide in thyroglobulin is not in iodothyronine; about 70% is in inactive compounds MIT and DIT.

4. Coupling of Iodotyrosines:

Now, within thyroglobulin molecules, either DIT is oxidatively coupled with another DIT resi­due to form T₄ or a DIT is oxidatively coupled with a MIT to form T₃. The cou­pling is mediated by thyroperoxidase again. During this coupling, an alanine is cleaved off, which is later catabolized to pyruvate and ammonia.

5. Uptake and Proteolysis of Thyroglobu­lin:

Thyroid follicular cells then pinocytoze the colloid from follicular lu­men. The droplets coalesce with lysosomes. Lysosomal secretion contains proteases, glycoside hydrolyase and endo-peptidases. Lysosomal secretions hydrolyze thyroglobulin to release T₄, DIT and MIT.

T₄ and T₃ pass to blood by fa­cilitated diffusion through follicular cell membrane but DIT and MIT de-iodinated by microsomal deiodinase. The liberated iodine is reused for iodination of tyrosine (Fig. 6.5 and Fig. 6.6).

Transport of T₃ and T₄ Hormones:

Only small amounts of T₃ and T₄ (less than 1% of the T₃ and less than 0.1% of the T₄) are transported in free state in blood plasma. The major amounts are transported in bind­ing with plasma protein. T₄ remains bind with thyroxine binding globulin (TBG), thyroxine binding pre-albumin (TBPA) and serum albu­min. T₃ is transported through TBG only. Both T₃ and T₄ are carried through blood to tis­sues. Most T₃ (about 80%) in blood however, comes from de-iodination of T₄ in peripheral tissues and not directly from the thyroid gland itself.

Catabolism of T₃ and T₄ Hormones:

The liver and kidneys are the chief organs concerned in the catabolism of thyroid hor­mones. In the liver, maximum amounts are de-iodinated by enzyme deiodinase and then excreted in the bile and urine as glucuronates, sulfates and methyl conjugates. Both free and conjugated forms of thy­roxine are excreted in small amounts through the kidneys. In case of T₃, 80% is de-iodinated and 20% is excreted through faeces.

Control of Secretion of T₃ and T₄ Hormones:

T_s and T₄ synthesis and secretion are chiefly controlled by coordination of hypothalamus and adenohypophysis. On stimulation TSH- RH is secreted from hypothalamus and then stimulates adenohypophysis to secrete TSH which in turn stimulates thyroid follicular cells for secretion of T₃ and T₄.

The secretion of TSH-RH is inhibited by hyper secretion of TSH by negative feedback mechanism. The excess secretion of T₃ and T₄ control the secretion of TSH by negative feedback mechanism (Fig. 6.7).

Certain anti-thyroid drugs like thiourea, thiouracil etc. inhibit the thyroxine synthe­sis.