Thyroid hormone receptors TRα and TRβ

添加海藻氨酸（T3，100 nM）后，过度表达 TRβ1 的妊娠细胞会增殖 [1]。人 β1 甲状腺激素受体 (hTRβ1) 的结构构象因石氨酸与其结合而改变。碘塞罗宁可以刺激循环、控制新陈代谢并促进生长[2]。

为了了解人类β1甲状腺激素受体（h-TRβ1）激素依赖性转录调控的结构基础，我们研究了3,3'，5-三碘-L-甲状腺素（T3）结合诱导的h-TRβ-1的构象变化。h-TRβ1单独用胰蛋白酶处理或在T3、甲状腺激素反应元件（TRE）或T3与TRE一起存在的情况下处理。在没有T3的情况下，h-TRβ1被胰蛋白酶完全消化。TRE的结合对胰蛋白酶消化模式没有影响。然而，T3结合的h-TRβ1对胰蛋白酶消化产生了抗性，并产生了分子量为28000和24000的胰蛋白酶抗性肽片段。胰凝乳蛋白酶消化也产生了T3保护的24Kd肽片段。使用抗h-TRβ1抗体和氨基酸测序，28Kd片段被鉴定为Ser202-Asp456。发现24Kd胰蛋白酶片段为Lys239-Asp456和Phe240-Asp456。24Kd的糜蛋白酶片段被鉴定为Lys235-Asp456。T3结合导致的结构变化可以作为调节h-TRβ1基因调节活性的转导信号[2]。

为了了解甲状腺激素核受体（TRs）在肝癌发生中的作用，我们对9种人肝癌细胞系中的TRs进行了表征。TR蛋白的表达依赖于受体亚型和细胞类型。TRα1蛋白在九个细胞系中的每一个中都以低水平类似地表达。相比之下，TRβ1在分化较差的肝癌细胞中过表达。此外，发现甲状腺激素刺激TRβ1过表达的细胞增殖。这些结果表明，TRβ1最有可能参与肝癌细胞的分化和增殖。我们的研究为理解TR在肝癌发生中的作用提供了新的思路[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

92.78

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

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。