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| 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) | |
| 2710227 | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| DrugBank |
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| ECHA InfoCard | 100.027.272 |
| EC Number |
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| KEGG | |
| UNII | |
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| Properties | |
| C15H12I3NO4 | |
| Molar mass | 650.977 g·mol−1 |
| Hazards | |
| GHS labelling: | |
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| Warning | |
| H315,H319,H335 | |
| P261,P264,P271,P280,P302+P352,P304+P340,P305+P351+P338,P312,P321,P332+P313,P337+P313,P362,P403+P233,P405,P501 | |
| NFPA 704 (fire diamond) | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Triiodothyronine, also known asT3, is athyroid hormone. It affects almost everyphysiological process in the body, includinggrowth and development,metabolism,body temperature, andheart rate.[1]
Production of T3 and itsprohormonethyroxine (T4) is activated bythyroid-stimulating hormone (TSH), which is released from the anterior pituitary gland. This pathway is part of a closed-loopfeedback process: Elevated concentrations of T3, and T4 in theblood 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, afeedback control system stabilizes the level of thyroid hormones in thebloodstream.
At the cellular level, T3 is the body's more active and potent thyroid hormone.[2] T3 helps deliver oxygen and energy to all of the body's cells, its effects on target tissues being 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. Thehalf-life of T3 is about 2.5 days.[3] The half-life of T4 is about 6.5 days.[4] T3 levels start to rise 45 minutes after administration and peak at about 2.5 hours. Although manufacturer of Cytomel states half-life to be 2.5 days the half-life variability is great and can vary depending on the thyroid status of the patient. Newer studies have found the pharmacokinetics of T3 to be complex and the half-life to vary between10 – 22 hours.[5]
T3 is the more metabolically active hormone produced from T4. T4 is deiodinated by threedeiodinase enzymes to produce the more-active triiodothyronine:
T4 is synthesised in thethyroid follicular cell as follows.
The thyroid gland also produces small amounts of T3 directly. In thefollicular lumen,tyrosine residues become iodinated. This reaction requireshydrogen peroxide. Iodine bonds carbon 3 or carbon 5 of tyrosine residues of thyroglobulin in a process calledorganification of iodine. The iodination of specific tyrosines yieldsmonoiodotyrosine (MIT) anddiiodotyrosine (DIT). One MIT and one DIT are enzymatically coupled to form T3. The enzyme isthyroid 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.[7] This once again raises the question if T3 should be included in thyroid hormone replacement therapy (THRT).
T3 and T4 bind tonuclear receptors (thyroid hormone receptors).[8] T3 and T4, although being lipophilic, are not able to passively diffuse through the phospholipid bilayers of target cells,[9] instead relying on transmembraneiodothyronine transporters. The lipophilicity of T3 and T4 requires their binding to the protein carrier thyroid-binding protein (TBG) (thyroxine-binding globulins,thyroxine binding prealbumins, andalbumins) 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.
T3 and T4 are carried in the blood, bound to plasma proteins. This has the effect of increasing thehalf-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 toserum albumin, but, due to the large availability of albumin, it has a high capacity.
The saturation of binding spots onthyronine-binding globulin (TBG) by endogenous T3 can be estimated by thetriiodothyronine resin uptake test. The test is performed by taking ablood 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.[11]
T3 increases thebasal 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 synthesis and activity of theNa+/K+-ATPase (which normally constitutes a substantial fraction of total cellular ATP expenditure) without disrupting transmembrane ion balance.[12] In general, it increases the turnover of different endogenous macromolecules by increasing their synthesis and degradation.
Thyroid hormones are essential for normal growth and skeletal maturation.[13] They potentiate the effect ofgrowth hormone andsomatomedins to promotebone growth,epiphysial closure andbone maturation.[12][13]
T3 stimulates the production ofRNA 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.[further explanation needed]
T3 stimulates the breakdown of cholesterol and increases the number of LDL receptors, thereby increasing the rate oflipolysis.
T3 increases the heart rate and force of contraction, thus increasingcardiac output, by increasing β-adrenergic receptor levels in myocardium.[14] This results in increasedsystolic blood pressure and decreaseddiastolic blood pressure. The latter two effects act to produce the typicalbounding pulse seen inhyperthyroidism.[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 inhyperthyroidism.
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 ofmyelin, the production ofneurotransmitters, and the growth of axons. It is also important in the linear growth of bones.
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 reversedlearned helplessness in rats and physiological studies of the rat brain.[15]
Thyroid hormones act to increase protein turnover. This might serve an adaptive function in regard to long-term calorie restriction with adequate protein.[16][17] When calories are in short supply, reduction in protein turnover may ameliorate the effects of the shortage.
Triiodothyronine can be measured asfree triiodothyronine, which is an indicator of triiodothyronine activity in the body. It can also be measured astotal triiodothyronine, which also depends on the triiodothyronine that is bound tothyroxine-binding globulin.[18]
T4 (levothyroxine) is almost always preferred over T3 (liothyronine) when treatinghypothyroidism. Treatment with T3 alone is not recommended, as it causes increased and potentially unsafe blood levels of free T3 (FT3). Combination treatment of hypothyroidism with T4 and T3 is generally only considered when treatment with T4 alone does not sufficiently resolve symptoms. As there is no evidence showing that combination treatment with T4 and T3 benefits patients, this approach is controversial, but it is supported by current guidelines of theEuropean Thyroid Association and theBritish Thyroid Association for patients who do not respond at all to treatment with T4 alone.[19]
The addition of triiodothyronine to existing treatments such asSSRIs is one of the most widely studied augmentation strategies forrefractory depression,[20] 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.[20] The same authors published a retrospective study of 125 patients with the two most common categories ofbipolar disordersII andNOS 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 months (standard deviation of 9.7). None of the patients experienced hypomania while on T3.[21]
3,5-Diiodo-L-thyronine and3,3′-diiodo-L-thyronine are used as ingredients in certain over-the-counter fat-loss supplements, designed forbodybuilding. Several studies have shown that these compounds increase the metabolization of fatty acids and the burning of adipose fat tissue in rats.[22][23]
Triiodothyronine has been used to treatWilson's syndrome, analternative medical diagnosis not recognized as a medical condition bymainstream medicine. This diagnosis involves variousnon-specific symptoms that are attributed to the thyroid, despite normalthyroid function tests. TheAmerican Thyroid Association has raised concern that the prescribed treatment with triiodothyronine is potentially harmful.[24]
In 1950,Jack Gross, a Canadian endocrinologist, came to the BritishNational Institute for Medical Research to work withRosalind Pitt-Rivers as a postdoctoral fellow. Gross had previous experience working atMcGill University under ProfessorCharles Leblond, where they usedradioactive iodine to study the physiology of thyroid hormone and applied chromatography to analyze radioiodinated proteins in human blood after radioiodine therapy. Gross and Leblond found an unknown radioactive compound in the blood of rats given radioactive iodine. The compound migrated close to thyroxine in chromatography and they initially named it 'unknown 1'. Around that time a group led by Jean Roche in Paris described a deiodinating activity in the sheep thyroid gland, raising the possibility that 'unknown 1' is the less iodinated analogue of T4, triiodothyronine.[25] In March of 1952, Gross and Pitt-Rivers published a paper inThe Lancet titled "The identification of 3: 5: 3'-L-triiodothyronine in human plasma".[26]
While Gross & Pitt-Rivers are normally credited with discovering T3, this compound was actually first isolated by the biochemistsHird andTrikojus at the University of Melbourne in 1948.[27] It has been suggested that their published paper was little-known and therefore easily ignored.[28] It has also been stated that Pitt-Rivers had read this paper but failed to mention it.[29]
Between 2020 and 2024, in numerous studies, an association was observed between serum free triiodothyronine (fT3) concentrations and the prognosis of severe COVID-19 in patients with SARS-CoV-2 infection. Serum fT3 concentrations are significantly lower in patients with severe COVID-19 compared to those who are not severely ill, and they predict all-cause mortality in patients with severe COVID-19.[30][31][32][33][34]
