Triiodothyronine
IUPAC name (2S)-2-amino-3- [4-(4-hydroxy-3-iodo-phenoxy)- 3,5-diiodo-phenyl]propanoic acid
Other names triiodothyronine T3 3,3',5-triiodo-L-thyronine
Identifiers
CAS number	6893-02-3 Y
ChemSpider	5707 Y
UNII	06LU7C9H1V Y
DrugBank	DB00279
ChEBI	CHEBI:18258 Y
ChEMBL	CHEMBL1544 Y
Jmol-3D images	Image 1
SMILES c1cc(c(cc1Oc2c(cc(cc2I)C[C@@H](C(=O)O)N)I)I)O
InChI InChI=1S/C15H12I3NO4/c16-9-6-8(1-2-13(9)20)23-14-10(17)3-7(4-11(14)18)5-12(19)15(21)22/h1-4,6,12,20H,5,19H2,(H,21,22)/t12-/m0/s1 Y Key: AUYYCJSJGJYCDS-LBPRGKRZSA-N Y InChI=1/C15H12I3NO4/c16-9-6-8(1-2-13(9)20)23-14-10(17)3-7(4-11(14)18)5-12(19)15(21)22/h1-4,6,12,20H,5,19H2,(H,21,22)/t12-/m0/s1 Key: AUYYCJSJGJYCDS-LBPRGKRZBY
Properties
Molecular formula	C15H12I3NO4
Molar mass	650.9776 g mol−1
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
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]

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

As the true hormone, the effects of T₃ 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 thyroid 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. This is observed in fact because of the short half-life of T₃, which is only 2.5 days.^[3] This compares with the half-life of T₄, which is about 6.5 days.

[edit] Production of T₃

Thyroid hormone synthesis, with the end-product of triiodothyronine seen at bottom right.^[4]

T₃ is the more metabolically active hormone produced from T₄. T₄ is deiodinated by two deiodinase enzymes to produce the more-active triiodothyronine:
1. Type I present within the liver and accounts for 80% of the deiodination of T₄
2. Type II present within the pituitary gland.

T₄ is synthesised in the thyroid gland follicular cells as follows.
1. The Na⁺/I^- 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 membranae 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 pituitary gland binds the TSH receptor ( a G_s 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.

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.

Synthesis

Mechanism of action[link]

The T₃ (and T₄) bind to nuclear receptors, thyroid receptors. T₃ (and T₄) are very lipophilic and able to pass through the phospholipid bilayers of target cells. 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.

The transportation of triiodothyronine[link]

The system of the thyroid hormones T3 and T4.^[5]

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. Thyronine-binding globulin (TBG) is a glycoprotein that has a higher affinity for T₄ than for T₃. Transthyretin is also a glycoprotein, but with a higher affinity for T₃ than for T₄. Finally, both hormones bind with a low affinity to serum albumin, but, due to the large availability of albumin, it has a high capacity.

[edit] Effects of T₃

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 and testis. It increases the production of the Na⁺/K⁺ -ATPase 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.

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.^[6] 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]}

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.^[7]

Measurement[link]

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.^[8]

[edit] T₃ in the 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,^[9] 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 mcg required to achieve therapeutic effect, with an average of 80 mcg and a dosage span of 24 months;dose range:25mcg-150mcg.^[9] 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 (standard deviation of 9.7). None of the patients experienced hypomania while on T₃.^[10]

Use as a fat loss supplement[link]

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.^[11][12]

Alternative medicine[link]

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.^[13]

References[link]

See also[link]

• Polar T3 syndrome

External links[link]

• Triiodothyronine bound to proteins in the PDB