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. From these hormones, liothyronine is almost completely absorbed and it does not present changes in the absorption rate due to concomitant administration of food.liothyronin Multiple administration of 50 mcg of liothyronine provided a maximal plasma concentration of total T3 of 346 ng/dL in about 2.5 hours with an AUC of 4740 ng.h/dL.
The main elimination of thyroid hormones is known to be done via the kidneys from which less than 2.5% of the excreted drug is represented by the unchanged drug. This elimination route is reduced with age. A portion of the metabolic products of liothyronine is excreted to the bile and gut where they can be part of enterohepatic recirculation.
The reported volume of distribution of liothyronine is reported to be of 0.1-0.2 L/kg.
There are no reports obtaining this value specifically.
WHILE TRIIODOTHYRONINE IS MUCH LESS FIRMLY BOUND /TO PROTEIN THAN IS THYROXINE/, THE QUANTITY THAT IS FREE IS STILL SMALL PERCENTAGE OF TOTAL.
THE DAILY SECRETION OF /TRIIODOTHYRONINE/ IN NORMAL MAN IS APPROXIMATELY...25 UG.
LIOTHYRONINE IS ERRATICALLY ABSORBED FROM GI TRACT, & 30 TO 40% MAY BE RECOVERED FROM STOOLS.
INTESTINAL ABSORPTION OF THYROID HORMONES WERE MARKEDLY DIMINISHED AFTER INTESTINAL BYPASS SURGERY & RESTORED TO NORMAL AFTER REVERSAL OF SHUNT.
Liothyronine sodium is almost completely absorbed from the GI tract (about 95%) following oral administration. /Liothyronine sodium/

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Metabolism / Metabolites
Liothyronine is mainly metabolized in the liver where it is deiodinated to diiodothyronine and monoiodothyronine followed by conjugation with glucuronides and sulfates. One of the formed metabolites formed by the conjugation and decarboxylation is tiratricol. The iodine released by the metabolism of liothyronine is later taken and used within the thyroid cells.
THE LIVER CONJUGATES THYROXINE & TRIIODOTHYRONINE WITH GLUCURONIC & SULFURIC ACIDS THROUGH THE PHENOLIC HYDROXYL GROUP, & EXCRETES THESE CONJUGATES & SMALL AMT OF FREE COMPOUNDS IN THE BILE.
Triiodothyronine has known human metabolites that include (2S,3S,4S,5R)-6-[4-[4-[(2S)-2-amino-2-carboxyethyl]-2,6-diiodophenoxy]-2-iodophenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid.
Half Life: 2.5 days

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Biological Half-Life
The half-life of liothyronine is reported to be between 1 and 2 days.

Toxicity Summary
The hormones, T₄ and T₃, are tyrosine-based hormones produced by the thyroid gland. Iodine is an important component in their synthesis. The major form of thyroid hormone in the blood is thyroxine (T₄). This is converted to the more active liothyronine form by deiodinases in peripheral tissues. Liothyronine acts on the body to increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline). The thyroid hormones are essential to proper development and differentiation of all cells of the human body. To various extents T₄ and T₃ regulate protein, fat and carbohydrate metabolism. Their most pronounced effect is on how human cells use energetic compounds. The thyroid hormone derivatives bind to the thyroid hormone receptors initially to initiate their downstream effects.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Liothyronine (T3) is a normal component of human milk. If replacement doses of liothyronine are required by the mother, it is not necessarily a reason to discontinue breastfeeding. However, because no information is available on the use of exogenous liothyronine during breastfeeding, an alternate drug may be preferred. The American Thyroid Association recommends that subclinical and overt hypothyroidism should be treated with levothyroxine in lactating women seeking to breastfeed. Liothyronine dosage requirement may be increased in the postpartum period compared to prepregnancy requirements patients with Hashimoto's thyroiditis.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date. However, the thyroid hormone content of human milk from the mothers of very preterm infants appears not to be sufficient to affect the infant’s thyroid status.
◉ Effects on Lactation and Breastmilk
Adequate thyroid hormone serum levels are required for normal lactation. Replacing deficient thyroid levels should improve milk production caused by hypothyroidism. Supraphysiologic doses of liothyronine would not be expected to further improve lactation.

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Protein Binding
Liothyronine presents a very large binding to plasma proteins and around 99.7% of the administered dose can be found bound. Liothyronine is found to be bound to thyroxine-binding globulin, thyroxine-binding prealbumin and albumin. It is important to consider that only the little unbound portion of liothyronine is metabolically active.

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Interactions
USE OF PROPRANOLOL IN CONJUNCTION WITH REPLACEMENT THERAPY HAS BEEN REPORTED TO DECR RISK OF ARRHYTHMIA & ANGINA...
THYROID COMPOUNDS THAT PRODUCE HYPERMETABOLIC STATE (LIOTHYRONINE...) INCR RATE OF DECAY OF VITAMIN K-DEPENDENT CLOTTING FACTORS, & IN PRESENCE OF ORAL ANTICOAGULANTS /EG, WARFARIN/, NORMAL COMPENSATION BY INCR SYNTHESIS IS PREVENTED.
THERE IS CONSIDERABLE CLINICAL EVIDENCE THAT A PATIENT'S THYROID STATE AFFECTS RESPONSE TO TRICYCLIC ANTIDEPRESSANT DRUGS. ADDITION OF LIOTHYRONINE (25 UG/DAY) MAY PREVENT RELATIVELY LONG LAG TIME THAT OCCURS BEFORE CLINICAL EFFECTIVENESS OF TRICYCLIC ANTIDEPRESSANTS IS OBSERVED.
CHOLESTYRAMINE MAY CAUSE CLINICALLY SIGNIFICANT DECR IN ABSORPTION OF THYROID HORMONE WHEN THESE DRUGS ARE GIVEN SIMULTANEOUSLY. /THYROID HORMONE/
For more Interactions (Complete) data for LIOTHYRONINE (16 total), please visit the HSDB record 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
LIOTHYRONINE SODIUM...MAY BE USEFUL...WHEN HYPOTHYROIDISM HAS RECENTLY SUPERVENED FROM OVERTREATMENT WITH ANTITHYROID DRUG OR FOLLOWING TREATMENT WITH RADIOIODINE OR THYROIDECTOMY, & IN RARE EVENT OF COMA DUE TO MYXEDEMA. /LIOTHYRONINE SODIUM/
WITH THIS DOSE /EXPERIMENTAL DOSE OF 1 MG SC ADMIN/, A METABOLIC RATE OF MINUS 40% CAN BE RAISED TO NORMAL WITHIN 24 HR. MAXIMAL RESPONSE OCCURS IN 2 DAYS OR LESS.
Triiodothyronine (liothyronine sodium) may be used occasionally when a quicker onset of action is desired as, for example, in the rare presentation of myexedema coma or for preparing a patient for (131)I therapy for treatment of thyroid cancer.
MEDICATION (VET):: USED FOR...OBESITY, BILATERAL ALOPECIA, ACANTHOSIS, DRY SKIN, WRINKLED SKIN, POOR HAIR COLOR, STRAIGHTNESS IN CURLY HAIR COATS, LACK OF "WIRE" IN WIRE-HAIRED BREEDS, LETHARGY, SLOW GROWTH, UNTHRIFTINESS, LIBIDO LOSS, POOR BREEDING EFFICIENCY, URINARY INCONTINENCE, & LACK OF MENTAL & PHYSICAL VIGOR ESP IN OLDER ANIMALS.
For more Therapeutic Uses (Complete) data for LIOTHYRONINE (12 total), please visit the HSDB record page.

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Drug Warnings
VET: AVOID EXCESSIVE DOSAGE IN CASES WITH WEAK HEARTS.
LIOTHYRONINE LABELED WITH EITHER (125)I OR (131)I...FOR IN VITRO EVALUATION OF THYROID FUNCTION. DUE TO HIGH SPECIFIC ACTIVITY REQUIRED, RADIATION DAMAGE CAN EASILY OCCUR. ... DOSE IS NOT FOR INTERNAL USE.
IN ABSENCE OF HYPERTHYROIDISM, THYROID HORMONES DO NOT IMPROVE SKIN CONDITIONS, MENTAL DEPRESSION, FATIGUE, LETHARGY, IRRITABILITY, NERVOUSNESS, MENSTRUAL IRREGULARITIES, & OTHER ENDOCRINE & REPRODUCTIVE DISORDERS, & THERE IS DANGER THAT UNTOWARD EFFECTS MAY BE PRODUCED.
...THYROID HORMONES /EG, LIOTHYRONINE/ OR MIXTURES CONTAINING THEM SHOULD NOT BE USED WITHOUT SPECIFIC INDICATION OF DEFICIENCY. ...TO EFFECT WEIGHT LOSS IN EUTHYROID OBESE INDIVIDUALS...THYROID HORMONES OR PREPN CONTAINING THEM SHOULD NOT BE USED FOR THIS PURPOSE.
For more Drug Warnings (Complete) data for LIOTHYRONINE (17 total), please visit the HSDB record page.

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Pharmacodynamics
In hormonal replacement, liothyronine is more potent and present a faster action when compared to levothyroxine but the time of action is significantly shorter. The type of treatment needs to be well evaluated as the fast correction of thyroid hormones in certain diseases presents additional risks such as heart failure. The onset of activity is observed a few hours after administration and the maximum effect is observed after 2-3 days. Treatment with liothyronine has been shown to produce normal plasma levels of T3 hormone but to have no effect on the T4 plasma 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.)