Triiodothyronine

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Triiodothyronine
Liothyronine2DCSD.svg
T3-3D-balls.png
Names
IUPAC name
(2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid
Other names
triiodothyronine
T3
3,3′,5-triiodo-L-thyronine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.027.272
UNII
Properties
C15H12I3NO4
Molar mass 650.977 g·mol−1
Hazards
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeTriiodothyronine
1
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. [1]

Contents

Production of T3 and its prohormone thyroxine (T4) is activated by thyroid-stimulating hormone (TSH), which is released from the anterior pituitary gland. This pathway is part of a closed-loop feedback process: Elevated concentrations of T3, and T4 in the blood plasma inhibit the production of TSH in the anterior pituitary gland. As concentrations of these hormones decrease, the anterior pituitary gland increases production of TSH, and by these processes, a feedback control system stabilizes the amount of thyroid hormones that are in the bloodstream.

T3 is the true hormone. Its effects on target tissues are roughly four times more potent than those of T4. [2] Of the thyroid hormone that is produced, just about 20% is T3, whereas 80% is produced as T4. Roughly 85% of the circulating T3 is later formed in the liver and anterior pituitary by removal of the iodine atom from the carbon atom number five of the outer ring of T4. In any case, the concentration of T3 in the human blood plasma is about one-fortieth that of T4. The half-life of T3 is about 2.5 days. [3] The half-life of T4 is about 6.5 days. [4]

Production

Synthesis from T4

Thyroid hormone synthesis, with the end-product of triiodothyronine seen at bottom right. Thyroid hormone synthesis.png
Thyroid hormone synthesis, with the end-product of triiodothyroninе seen at bottom right.

T3 is the more metabolically active hormone produced from T4. T4 is deiodinated by three deiodinase enzymes to produce the more-active triiodothyronine:

  1. Type I present in liver, kidney, thyroid, and (to a lesser extent) pituitary; it accounts for 80% of the deiodination of T4.
  2. Type II present in CNS, pituitary, brown adipose tissue, and heart vessel, which is predominantly intracellular. In the pituitary, it mediates negative feedback on thyroid-stimulating hormone.
  3. Type III present in placenta, CNS, and hemangioma. This deiodinase converts T4 into reverse T3, which, unlike T3, is inactive.

T4 is synthesised in the thyroid gland follicular cells as follows.

  1. The sodium-iodide symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodine ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I against its concentration gradient.
  2. I is moved across the apical membrane into the colloid of the follicle.
  3. Thyroperoxidase oxidises two I to form I2. Iodide is non-reactive, and only the more reactive iodine is required for the next step.
  4. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.
  5. Thyroid-stimulating hormone (TSH) released from the anterior pituitary gland binds the TSH receptor (a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
  6. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin.
  7. These vesicles are then exocytosed, releasing the thyroid hormones.
Synthesis of T3 from T4 via deiodination. Synthesis of reverse T3 and T2 is also shown. Iodothyronine deiodinase.png
Synthesis of T3 from T4 via deiodination. Synthesis of reverse T3 and T2 is also shown.

Direct synthesis

The thyroid gland also produces small amounts of T3 directly. In the follicular lumen, tyrosine residues become iodinated. This reaction requires hydrogen peroxide. Iodine bonds carbon 3 or carbon 5 of tyrosine residues of thyroglobulin in a process called organification of iodine. The iodination of specific tyrosines yields monoiodotyrosine (MIT) and diiodotyrosine (DIT). One MIT and one DIT are enzymatically coupled to form T3. The enzyme is thyroid peroxidase.

The small amount of T3 could be important because different tissues have different sensitivities to T4 due to differences in deiodinase ubiquitination in different tissues link. This once again raises the question if T3 should be included in thyroid hormone replacement therapy (THRT).

Mechanism of action

T3 and T4 bind to nuclear receptors (thyroid hormone receptors). [6] T3 and T4, although being lipophilic, are not able to passively diffuse through the phospholipid bilayers of target cells, [7] instead relying on transmembrane iodothyronine transporters. The lipophilicity of T3 and T4 requires their binding to the protein carrier thyroid-binding protein (TBG) (thyroxine-binding globulins, thyroxine binding prealbumins, and albumins) for transport in the blood. The thyroid receptors bind to response elements in gene promoters, thus enabling them to activate or inhibit transcription. The sensitivity of a tissue to T3 is modulated through the thyroid receptors.

Transportation

The system of the thyroid hormones T3 and T4. Thyroid system.svg
The system of the thyroid hormones T3 and T4.

T3 and T4 are carried in the blood, bound to plasma proteins. This has the effect of increasing the half-life of the hormone and decreasing the rate at which it is taken up by peripheral tissues. There are three main proteins that the two hormones are bound to. Thyroxine-binding globulin (TBG) is a glycoprotein that has a higher affinity for T4 than for T3. Transthyretin is also a glycoprotein, but only carries T4, with hardly any affinity at all for T3. Finally, both hormones bind with a low affinity to serum albumin, but, due to the large availability of albumin, it has a high capacity.

The saturation of binding spots on thyronine-binding globulin (TBG) by endogenous T3 can be estimated by the triiodothyronine resin uptake test. The test is performed by taking a blood sample, to which an excess of radioactive exogenous T3 is added, followed by a resin that also binds T3. A fraction of the radioactive T3 binds to sites on TBG not already occupied by endogenous thyroid hormone, and the remainder binds to the resin. The amount of labeled hormones bound to the resin is then subtracted from the total that was added, with the remainder thus being the amount that was bound to the unoccupied binding sites on TBG. [9]

Effects

T3 increases the basal metabolic rate and, thus, increases the body's oxygen and energy consumption. The basal metabolic rate is the minimal caloric requirement needed to sustain life in a resting individual. T3 acts on the majority of tissues within the body, with a few exceptions including the spleen. It increases the production of the Na+/K+ -ATPase (which normally constitutes a substantial fraction of total cellular ATP expenditure) without disrupting transmembrane ion balance and, in general, increases the turnover of different endogenous macromolecules by increasing their synthesis and degradation.

Protein

T3 stimulates the production of RNA Polymerase I and II and, therefore, increases the rate of protein synthesis. It also increases the rate of protein degradation, and, in excess, the rate of protein degradation exceeds the rate of protein synthesis. In such situations, the body may go into negative ion balance.

Glucose

T3 potentiates the effects of the β-adrenergic receptors on the metabolism of glucose. Therefore, it increases the rate of glycogen breakdown and glucose synthesis in gluconeogenesis.[ citation needed ]

Lipids

T3 stimulates the breakdown of cholesterol and increases the number of LDL receptors, thereby increasing the rate of lipolysis.

Heart

T3 increases the heart rate and force of contraction, thus increasing cardiac output, by increasing β-adrenergic receptor levels in myocardium. [10] This results in increased systolic blood pressure and decreased diastolic blood pressure. The latter two effects act to produce the typical bounding pulse seen in hyperthyroidism. [ citation needed ] It also upregulates the thick filament protein myosin, which helps to increase contractility. A helpful clinical measure to assess contractility is the time between the QRS complex and the second heart sound. This is often decreased in hyperthyroidism.

Development

T3 has profound effect upon the developing embryo and infants. It affects the lungs and influences the postnatal growth of the central nervous system. It stimulates the production of myelin, the production of neurotransmitters, and the growth of axons. It is also important in the linear growth of bones.

Neurotransmitters

T3 may increase serotonin in the brain, in particular in the cerebral cortex, and down-regulate 5HT-2 receptors, based on studies in which T3 reversed learned helplessness in rats and physiological studies of the rat brain. [11]

Physiological function

Thyroid hormones act to increase protein turnover. This might serve an adaptive function in regard to long-term calorie restriction with adequate protein. [12] [13] When calories are in short supply, reduction in protein turnover may ameliorate the effects of the shortage.

Measurement

Triiodothyronine can be measured as free triiodothyronine, which is an indicator of triiodothyronine activity in the body. It can also be measured as total triiodothyronine, which also depends on the triiodothyronine that is bound to thyroxine-binding globulin. [14]

Uses

Treatment of depressive disorders

The addition of triiodothyronine to existing treatments such as SSRIs is one of the most widely studied augmentation strategies for refractory depression, [15] however success may depend on the dosage of T3. A long-term case series study by Kelly and Lieberman of 17 patients with major refractory unipolar depression found that 14 patients showed sustained improvement of symptoms over an average timespan of two years, in some cases with higher doses of T3 than the traditional 50 µg required to achieve therapeutic effect, with an average of 80 µg and a dosage span of 24 months; dose range: 25-150 µg. [15] The same authors published a retrospective study of 125 patients with the two most common categories of bipolar disorders II and NOS whose treatment had previously been resistant to an average of 14 other medications. They found that 84% experienced improvement and 33% experienced full remission over a period of an average of 20.3[ clarification needed ] (standard deviation of 9.7). None of the patients experienced hypomania while on T3. [16]

Use as a fat loss supplement

3,5-Diiodo-L-thyronine and 3,3′-diiodo-L-thyronine are used as ingredients in certain over-the-counter fat-loss supplements, designed for bodybuilding. Several studies have shown that these compounds increase the metabolization of fatty acids and the burning of adipose fat tissue in rats. [17] [18]

Alternative medicine

Triiodothyronine has been used to treat Wilson's syndrome, an alternative medical diagnosis not recognized as a medical condition by mainstream medicine. This diagnosis involves various non-specific symptoms that are attributed to the thyroid, despite normal thyroid function tests. The American Thyroid Association has raised concern that the prescribed treatment with triiodothyronine is potentially harmful. [19]

See also

Related Research Articles

Thyroid endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid gland, or simply the thyroid, is an endocrine gland in the neck, consisting of two lobes connected by an isthmus. It is found at the front of the neck, below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with thyroid follicular cells and occasional thyroid parafollicular cells surrounding thyroid colloid. The thyroid gland secretes three hormones: the two thyroid hormones, thyroxine/T4 and triiodothyronine/T3; and calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis, and in children, growth and development. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

Graves disease Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 80% of people with the condition develop eye problems.

Hypothyroidism Endocrine disease

Hypothyroidism, also called underactive thyroid or low thyroid, is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Untreated hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Iodothyronine deiodinase class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid. In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance.

Thyroxine-binding globulin (TBG) is a globulin that binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.

Thyroglobulin mammalian protein found in Homo sapiens

Thyroglobulin (Tg) is a 660 kDa, dimeric glycoprotein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Thyroglobulin protein accounts for approximately half of the protein content of the thyroid gland. Human TG (HTG) is a homodimer of subunits each containing 2768 amino acids as synthesized.

Follicular cell

Follicular cells are the major cell type in the thyroid gland and are responsible for the production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Thyroid hormone resistance Human disease

Thyroid hormone resistance describes a rare syndrome in which the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, or not completely suppressed as would be expected. The first report of the condition appeared in 1967. Essentially this is decreased end organ responsiveness to thyroid hormones. A new term "impaired sensitivity to thyroid hormone" has been suggested in March 2014 by Refetoff et al.

Endocrine gland

Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary gland are neuroendocrine organs.

Thyroid disease type of endocrine disease

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Liothyronine chemical compound, salt of a drug

Liothyronine is a manufactured form of the thyroid hormone triiodothyronine (T3). It is most commonly used to treat hypothyroidism and myxedema coma. It is generally less preferred than levothyroxine. It can be taken by mouth or by injection into a vein.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcriptionand translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

Thyrotropin receptor mammalian protein found in Homo sapiens

The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

clinically euthyroid patients do not have elevated thyroid-stimulating hormone (TSH) levels. Pathogenesis is unknown but may include decreased peripheral conversion of T4 to T3, decreased clearance of rT3 generated from T4, and decreased binding of thyroid hormones to thyroxine-binding globulin (TBG).

Hypothalamic–pituitary–thyroid axis part of the neuroendocrine system responsible for the regulation of metabolism.

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamsus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences and impaired assay characteristics in critical illness.

Thyroid hormones hormones produced by the thyroid gland

Thyroid hormones are two hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.

Deiodinase is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

References

  1. Bowen, R. (2010-07-24). "Physiologic Effects of Thyroid Hormones". Colorado State University. Retrieved 2013-09-29.
  2. "How Your Thyroid Works – "A delicate Feedback Mechanism"". endocrineweb. 2012-01-30. Retrieved 2013-09-29.
  3. "Cytomel (Liothyronine Sodium) Drug Information". RxList. 2011-01-03. Retrieved 2013-09-29.
  4. Irizarry, Lisandro (23 April 2014). "Thyroid Hormone Toxicity". Medscape. WedMD LLC. Retrieved 2 May 2014.
  5. Boron, W. F. (2005). Medical Physiology: A Cellular And Molecular Approach. Philadelphia, PA: Elsevier / Saunders. p. 1300. ISBN   1-4160-2328-3. LCCN   2004051158.
  6. Lazar, MA; Chin, WW (December 1990). "Nuclear thyroid hormone receptors". J. Clin. Invest. 86: 1777–1782. doi:10.1172/JCI114906. PMC   329808 . PMID   2254444.
  7. Dietrich, J. W.; Brisseau, K.; Boehm, B. O. (2008). "Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen" [Absorption, transport and bio-availability of iodothyronines]. Deutsche Medizinische Wochenschrift (in German). 133 (31–32): 1644–1648. doi:10.1055/s-0028-1082780. PMID   18651367.
  8. References used in image are found in image article in Commons:Commons:File:Thyroid_system.png#References.
  9. triiodothyronine resin uptake test from Farlex Medical Dictionary, citing: Mosby's Medical Dictionary, 8th edition. 2009, Elsevier.
  10. "Thyroid physiology and tests of function". Anaesthetist.com.
  11. Martin, P.; Brochet, D.; Soubrie, P.; Simon, P. (1985). "Triiodothyronine-induced reversal of learned helplessness in rats". Biological Psychiatry. 20 (9): 1023–1025. doi:10.1016/0006-3223(85)90202-1. PMID   2992618.
  12. Fontana, L.; Klein, S.; Holloszy, J.O.; Premachandra, B.N. (2006). "Effect of long-term calorie restriction with adequate protein and micronutrients". J. Clin. Endocrinol. Metab. 91 (8): 3232–3235. doi:10.1210/jc.2006-0328. PMID   16720655.
  13. Roth, G.S.; Handy, A.M.; Mattison, J.A.; Tilmont, E.M.; Ingram, D.K.; Lane, M.A. (2002). "Effects of dietary calorie restriction and ageing on thyroid hormones of rhesus monkeys" (PDF). Horm. Metab. Res. 34 (7): 378–382. doi:10.1055/s-2002-33469.
  14. Military Obstetrics & Gynecology – Thyroid Function Tests In turn citing: Operational Medicine 2001, Health Care in Military Settings, NAVMED P-5139, May 1, 2001, Bureau of Medicine and Surgery, Department of the Navy, 2300 E Street NW, Washington, D.C., 20372-5300
  15. 1 2 Kelly, T. F.; Lieberman, D. Z. (2009). "Long term augmentation with T3 in refractory major depression". Journal of Affective Disorders. 115 (1–2): 230–233. doi:10.1016/j.jad.2008.09.022. ISSN   0165-0327. PMID   19108898.
  16. Kelly, T. F.; Lieberman, D. Z. (2009). "The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS". Journal of Affective Disorders. 116 (3): 222–226. doi:10.1016/j.jad.2008.12.010. PMID   19215985.
  17. Lombardi, A.; Lanni, A.; Moreno, M.; Brand, M. D.; Goglia, F. (1998). "Effect of 3,5-di-iodo-L-thyronine on the mitochondrial energy-transduction apparatus". The Biochemical Journal . 330 (1): 521–526. doi:10.1042/bj3300521. PMC   1219168 . PMID   9461551.
  18. Lanni, A. (2005). "3,5-Diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats". The FASEB Journal. 19 (11): 1552–1554. doi:10.1096/fj.05-3977fje. ISSN   0892-6638. PMID   16014396.
  19. "ATA Statement on "Wilson's Syndrome"". American Thyroid Association.