Thyroid hormone receptors TRα and TRβ

Pregnant cells overexpressing TRβ1 proliferate when ligothyronine (T3, 100 nM) is added [1]. The structural conformation of the human β1 thyroid hormone receptor (hTRβ1) is altered by lithyronine binding to it. Liothyronine can stimulate circulation, control metabolism, and encourage growth [2].

To understand the structural basis in the hormone-dependent transcriptional regulation of human beta 1 thyroid hormone receptor (h-TR beta 1), we studied the conformational changes of h-TR beta 1 induced by binding of 3,3',5-triiodo-L-thyronine (T3). h-TR beta 1 was treated with trypsin alone or in the presence of T3, thyroid hormone response element (TRE) or T3 together with TREs. Without T3, h-TR beta 1 was completely digested by trypsin. Binding of TREs had no effect on the tryptic digestion pattern. However, T3-bound h-TR beta 1 became resistant to tryptic digestion and yielded trypsin-resistant peptide fragments with molecular weight of 28,000 and 24,000. Chymotryptic digestion also yielded a T3-protected 24 Kd peptide fragment. Using anti-h-TR beta 1 antibodies and amino acid sequencing, the 28 Kd fragment was identified to be Ser202-Asp456. The 24 Kd tryptic fragments were found to be Lys239-Asp456 and Phe240-Asp456. The 24 Kd chymotryptic fragment was identified to be Lys235-Asp456. The structural changes as a result of T3 binding could serve as a transducing signal to modulate the gene regulating activity of h-TR beta 1[2].

To understand the role of thyroid hormone nuclear receptors (TRs) in hepatocarcinogenesis, we characterized the TRs in nine human hepatocarcinoma cell lines. The expression of TR proteins is receptor subtype- and cell type-dependent. TR alpha 1 protein expresses similarly at a low level in each of the nine cell lines. In contrast, TR beta 1 is overexpressed in hepatocarcinoma cells which are poorly differentiated. Furthermore, thyroid hormone was found to stimulate the proliferation of cells in which TR beta 1 is overexpressed. These results suggest that TR beta 1 is most likely involved in the differentiation and proliferation of hepatocarcinoma cells. Our studies have shed new light in the understanding of the role of TRs in liver carcinogenesis[1].

Absorption, Distribution and Excretion
Thyroid hormones are well absorbed orally. Triiodothyronine (T3) is almost completely absorbed, and its absorption rate is not affected by co-administration with food. After multiple doses of 50 micrograms of T3, the peak plasma total T3 concentration reaches 346 ng/dL in approximately 2.5 hours, with an AUC of 4740 ng·h/dL. Thyroid hormones are primarily excreted via the kidneys, with less than 2.5% excreted unchanged. Renal excretion decreases with age. Some metabolites of T3 are excreted into the bile and intestines and participate in enterohepatic circulation. The reported volume of distribution of T3 is 0.1-0.2 L/kg. Specific values are currently unavailable. Although the binding affinity of T3 to proteins is much lower than that of thyroxine, its free amount still constitutes a small portion of the total. The normal daily secretion of T3 in adults is approximately 25 micrograms.
The absorption of triiodothyronine in the gastrointestinal tract is unstable, with approximately 30% to 40% being excreted in feces.
The absorption of thyroid hormones is significantly reduced after intestinal bypass surgery, but returns to normal after shunt reversal.
After oral administration, sodium triiodothyronine is almost completely absorbed by the gastrointestinal tract (approximately 95%). /Sodium Triiodothyronine/

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Metabolism/Metabolites
Triiodothyronine is primarily metabolized in the liver, first undergoing deiodination to produce diiodothyronine and monoiodothyronine, which then conjugate with glucuronide and sulfate. One of the metabolites formed by conjugation and decarboxylation is tilatrel. Iodine released from the metabolism of triiodothyronine is subsequently absorbed and utilized by thyroid cells.
The liver conjugates thyroxine and triiodothyronine with glucuronic acid and sulfate via phenolic hydroxyl groups, and excretes these conjugates and a small amount of free compounds via bile.
The known metabolites of triiodothyronine include (2S,3S,4S,5R)-6-[4-[4-[(2S)-2-amino-2-carboxyethyl]-2,6-diiodophenoxy]-2-iodophenoxy]-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid.
Half-life: 2.5 days

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Biological half-life
The half-life of triiodothyronine has been reported to be 1 to 2 days.

Toxicity Summary
Thyroid hormones, namely T4 and T3, are tyrosine hormones secreted by the thyroid gland. Iodine is an important component in their synthesis. The main form of thyroid hormone in the blood is thyroxine (T4). In peripheral tissues, thyroxine is converted to the more active triiodothyronine (T3) by deiodinases. Triiodothyronine acts on the body to increase the basal metabolic rate, affect protein synthesis, and enhance the body's sensitivity to catecholamines (such as adrenaline). Thyroid hormones are essential for the normal development and differentiation of all cells in the body. T4 and T3 regulate the metabolism of proteins, fats, and carbohydrates to varying degrees. Their most significant effect lies in how human cells utilize energy compounds. Thyroid hormone derivatives first bind to thyroid hormone receptors, thereby initiating their downstream effects. Effects During Pregnancy and Lactation ◉ Overview of Use During Lactation Triiodothyronine (T3) is a normal component of human breast milk. If a mother needs to supplement with triiodothyronine, this does not necessarily mean that breastfeeding must be stopped. However, since there is currently no information on the use of exogenous triiodothyronine during lactation, other medications may be preferred. The American Thyroid Association recommends that levothyroxine be used to treat subclinical and clinical hypothyroidism in breastfeeding women who plan to breastfeed. Patients with Hashimoto's thyroiditis may require an increased dose of triiodothyronine postpartum compared to their pre-pregnancy levels.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found. However, the thyroid hormone levels in the breast milk of mothers of extremely premature infants do not appear to be sufficient to affect the infant's thyroid function.
◉ Effects on lactation and breast milk
Adequate serum thyroid hormone levels are necessary for normal lactation. Thyroid hormone supplementation can improve insufficient milk production caused by hypothyroidism. Supraphysiological doses of triiodothyronine are not expected to further improve lactation.
Protein binding

Triiodothyronine has a very high binding rate to plasma proteins; approximately 99.7% of the administered dose is bound. Triiodothyronine can bind to thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin. Notably, only a small amount of free triiodothyronine is metabolically active.

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Interactions
Propranolol has been reported to reduce the risk of arrhythmias and angina when used in combination with replacement therapy…
Thyroid compounds that produce a hypermetabolic state (triiodothyronine…) accelerate the decay of vitamin K-dependent clotting factors and suppress the normal compensatory mechanism of increased synthesis in the presence of oral anticoagulants (e.g., warfarin).
There is substantial clinical evidence that a patient's thyroid status affects their response to tricyclic antidepressants. Adding riotironine (25 mcg) daily may help shorten the long delay before the onset of action of tricyclic antidepressants.
Concomitant use of cholestyramine with riotironine may result in a significant decrease in thyroid hormone absorption. /Thyroid Hormones/
For more complete data on drug interactions of riotironine (16 in total), please visit the HSDB records page.

[1]. Stimulation of proliferation by 3,3',5-triiodo-L-thyronine in poorly differentiated human hepatocarcinoma cells overexpressing beta 1 thyroid hormone receptor. Cancer Lett. 1994 Oct 14;85(2):189-94.

[2]. Conformational changes of human beta 1 thyroid hormone receptor induced by binding of 3,3',5-triiodo-L-thyronine. Biochem Biophys Res Commun. 1993 Aug 31;195(1):385-92.

[3]. Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia. Bioorg Med Chem. 2012 Jun 1;20(11):3622-34.

[4]. Repositioning liothyronine for cancer immunotherapy by blocking the interaction of immune checkpoint TIGIT/PVR. Cell Commun Signal. 2020 Sep 7;18(1):142.

Therapeutic Uses
Sodium triiodothyronine…may be useful in the following situations…when hypothyroidism has recently occurred due to an overdose of antithyroid drugs, radioactive iodine therapy, or post-thyroidectomy, and in rare cases of coma due to myxedema. /Sodium triiodothyronine/
At this dose (experimental dose is 1 mg subcutaneously), the metabolic rate can be restored to normal by -40% within 24 hours. Maximum efficacy may be seen in 2 days or less.
Triiodothyronine (Leothyroxine sodium) can be used in situations requiring rapid onset of action, such as in rare cases of myoedema coma, or in preparation for patients undergoing iodine-131 treatment for thyroid cancer.
Veterinary drugs: Used to treat…obesity, bilateral alopecia, acanthosis, dry skin, wrinkled skin, poor coat color, erect hair in curly-haired dogs, lack of “wiry” hair in wire-haired breeds, lethargy, slow growth, weakness, decreased libido, low reproductive efficiency, urinary incontinence, and mental and physical exhaustion. Especially suitable for older animals.
For more complete data on the therapeutic uses of triiodothyronine iodide (12 types), please visit the HSDB record page.

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Drug Warning
Veterinarians: Avoid overdose in animals with weak hearts.
Triiodothyronine iodide is labeled (125)I or (131)I…for in vitro assessment of thyroid function. Due to the requirement of high specific activity, radiation damage is possible.
…This product is not for internal use. In cases of non-hyperthyroidism, thyroid hormones do not improve skin condition, depression, fatigue, somnolence, irritability, nervousness, menstrual irregularities, or other endocrine and reproductive system disorders, and may cause adverse reactions. Thyroid hormones (e.g., triiodothyronine) or mixtures containing thyroid hormones should not be used unless there is a clear indication of thyroid hormone deficiency. For obese individuals with normal thyroid function, thyroid hormones or preparations containing thyroid hormones should not be used for weight loss. For more complete data on triiodothyronine (17 in total), please visit the HSDB record page. Pharmacodynamics: In hormone replacement therapy, triiodothyronine is more potent and has a faster onset of action than levothyroxine, but its duration of action is significantly shorter. Treatment regimens require careful evaluation because rapid correction of thyroid hormone levels in certain conditions, such as heart failure, carries additional risks. Onset of action is observed within hours of administration, with maximum efficacy reached after 2-3 days. Studies have shown that triiodothyronine treatment can restore plasma T3 hormone levels to normal, but has no effect on plasma T4 concentration.

C15H12I3NO4

650.9735

650.79

C, 27.68; H, 1.86; I, 58.48; N, 2.15; O, 9.83

6893-02-3

Liothyronine sodium;55-06-1;Liothyronine-13C9,15N;1213569-04-0;Liothyronine-13C6-1;1213431-76-5;Liothyronine sodium hydrate;345957-19-9;Liothyronine hydrochloride;6138-47-2; 6138-47-2 (HCl); 6893-02-3 (free)

5920

CRYSTALS

2.4±0.1 g/cm3

563.5±50.0 °C at 760 mmHg

234-238 °C(lit.)

294.6±30.1 °C

0.0±1.6 mmHg at 25°C

1.763

5.08

3

5

5

23

402

1

IC1C(=C(C([H])=C(C=1[H])C([H])([H])[C@@]([H])(C(=O)O[H])N([H])[H])I)OC1C([H])=C([H])C(=C(C=1[H])I)O[H]

AUYYCJSJGJYCDS-LBPRGKRZSA-N

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

(2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid

liothyronine; triiodothyronine; 3,3',5-Triiodo-L-thyronine; 6893-02-3; Liothyronin; Tresitope; 3,5,3'-triiodothyronine; 3,5,3'-Triiodo-L-thyronine;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~76.81 mM)
1M NaOH : 50 mg/mL (~76.81 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)