- Email: [email protected]
3,3′,5-Triiodothyronine
SUBCHAPTER 93A
3,30,5-Triiodothyronine Kiyoshi Yamauchi
Abbreviation: T3 Additional names: liothyronine, liothyronin, tresitope IUPAC Name: (2S)-2-amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3,5-diiodo-phenyl]propanoic acid CAS No. 6893-02-3 T3 is an active form of thyroid hormone (TH), which plays an important role in body control, including growth and development, metabolism, body temperature, and heart rate.
Discovery Jack Gross and Rosalind Pitt-Rivers identified T3 in human plasma as a more active component than thyroxine (T4), in 1952 [1]. Rat liver deiodinase 1 was described as the first deiodinase enzyme for THs in 1976 [2].
Structure Structural Features T3 is a derivative of amino acid tyrosine. T3 has one iodine atom in the phenolic ring and two in the tyrosyl ring.
TRα and THRB for TRβ, which are located on 17q11.2 and 3p24.2, respectively, in humans. By alternative splicing and usage of internal ATG as a translational initiation site, these genes produce variable isoforms in rats and mice (E-Figure 93A.1), five of which are T3-binding isoforms: α1, p43, β1, β2, and β3 (Figure 93A.2) [6]. The isoform p43 acts as a TR in the mitochondrial matrix. The others lack TH binding activity due to the replacement of the critical TH binding region in the C-terminal region of TRα1, and act as TR antagonists. These isoforms are differentially expressed, showing isoformspecific physiological roles with some level of redundancy. Variable actions of THs are generated by the diversity of THresponse elements (TREs) (Figure 93A.3) and heterodimeric partners of TRs as well as different isoforms of TRs. The core TREs sequence is the hexanucleotide half-site (A/G)GGT(C/ A/G)A. TRE half-sites are present in pairs: direct repeat, inverted repeat, and everted repeat. Retinoid X receptor (RXR), vitamin D3 receptor (VDR), and peroxisome proliferator-activated receptor (PPAR) are known as heterodimer partners. In mitochondria, the truncated form of TRα1, p43, binds to one of the highly related TREs in the D-loop region.
Properties Molecular formula, C15H12I3NO4; Mr 650.97; physical state: solid, odorless, and tasteless; water solubility: 3.96 mg/l at 37 C.
Synthesis and Release Synthesis Eighty percent of circulating T3 is generated from T4 by deiodinases 1 and 2 (DIO1 and DIO2) in peripheral tissues (ETable 93A.1). These enzymes are selenocysteine-dependent membrane proteins. However, T4 is also converted to various metabolites in addition to T3 by specifc enzymes [3] as shown in Figure 93A.1. Daily production rates of T3 are 48 nmol/ day/70 kg, respectively [4].
Gene and mRNA DIO1 and DIO2 are located on 1p33p32 and 14q24.224.3, respectively.
Receptors Structure and Subtype Nuclear TH receptors (TRs) function as T3-dependent transcription factors [5]. TRs are encoded by two genes: THRA for
Signal Transduction Pathways After T3 binding to TRs on TREs in TH-induced target genes, major conformational changes in the helix 12 in the ligand-binding domain occurs. This induces a coregulator switch from a corepressor complex to a coactivator complex. Major corepressors are nuclear receptor corepressor (N-CoR) and silencing mediator of retinoic acid and TR (SMRT), which can associate with histone deacetylase 3 (HDAC3) to form a complex resulting in a compact state of chromatin via HDAC activity. Coactivators, including steroid receptor coactivators (SRC/p160) family and TR-associated proteins (TRAP), have histone acetyltransferase (HAT) activity or can recruit HATs to create a relaxed state of chromatin. This facilitates the recruitment of general transcription factors and RNA polymerase II. Phosphorylation of TRβ1 at serine 142 by MAPK (ERK1/2) also accelerates the coregulator switch.
Agonists T3 and Triac are more potent agonists than T4. A derivative of Triac, GC-1, is a synthetic TRβ-selective agonist [7]. Tetrabromobisphenol A has weak agonist activity.
Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00217-8 © 2016 Elsevier Inc. All rights reserved.
495
P A R T I I I Lipophilic Hormones in Vertebrates
Figure 93A.1 T3 synthesis and various metabolic pathways of T4.
Figure 93A.2 Mammalian TR subtypes, and their domain structure and expression sites.
Figure 93A.3 Three types of TREs.
Antagonists A derivative of Triac, NH-3, is a synthetic antagonist [7]. Tetrabromobisphenol A shows weak antagonist activity.
Biological Functions Target Cells/Tissues and Functions THs control normal growth and development in bone and central nervous system, and regulate lipids in adipose tissue. THs 496
also increase the metabolic rate in most metabolically active tissues in mammals by increasing absorption of carbohydrates from intestine, protein breakdown in muscle, O2 dissociation from hemoglobin, and O2 consumption [4]. These TH effects can be divided into two mechanistically different actions: genomic actions mediated by nuclear TRs in the nucleus and nongenomic actions that occur at the plasma membrane, in cytoplasm, and at subcellular organelles. T3-regulated hepatic and HepG2 genes, which are determined by microarray analyses, are shown in E-Table 93A.2 and E-Figure 93A.2.
S U B C H A P T E R 9 3 A 3,30 ,5-Triiodothyronine Phenotype in Gene-Modified Animals Mice lacking TRα1 have abnormal heart function and decreased body temperature. Mice lacking both TRα1 and TRα2 have impaired postnatal development and decreased postnatal survival, whereas mice lacking the TRβ gene have mild dysfunction of the pituitarythyroid axis, and a deficit in auditory function and eye development. Knock-in mice harboring a C-terminal frameshifted TRβ have dysfunction of the pituitary-thyroid axis and the nervous system, abnormal regulation of cholesterol, neurological growth retardation, hearing loss, and thyrotoxic skeletal phenotype [5,6]. In an amphibian, transgenic Xenopus laevis overexpressing dominant negative TRα prevents coactivator recruitment. This affects proliferation of the jaw and brain, resorption of the gills and tail, and remodeling of the intestinal tract [8].
Pathophysiological Implications Clinical Implications A close relationship is found between more than 347 family members with TH resistance (Refetoff syndrome) and 124 different mutations in the TRβ gene. Symptoms of this disorder are increased TH with non-suppressible thyrotropin, goiter, short stature, decreased weight, tachycardia, hearing loss, attention deficit hyperactivity disorder, and dyslexia, but most patients are heterozygous and are euthyroid. Mutant proteins act as a dominant negative form of TRβ. In contrast, there have been no reports on TRα mutation in humans [5].
References 1. Gross J, Pitt-Rivers R. The identification of 3:5:30 -L-triiodothyronine in human plasma. Lancet. 1952;1:439441. 2. Visser TJ, Does-Tobe´ I, Docter R, et al. Subcellular localization of a rat liver enzyme converting thyroxine into tri-iodothyronine and possible involvement of essential thiol groups. Biochem J. 1976;157:479482. 3. Wu SY, Green WL, Huang WS, et al. Alternate pathways of thyroid hormone metabolism. Thyroid. 2005;15:943958. 4. Braverman LE, Utiger RD, (eds). Werner and Ingbar’s The Thyroid: A fundamental and clinical text. 7th ed. Philadelphia: Lippincott-Raven; 1996. 5. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31:139170. 6. Flamant F, Samarut J. Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab. 2003;14:8590. 7. Webb P, Nguyen NH, Chiellini G, et al. Design of thyroid hormone receptor antagonists from first principles. J Steroid Biochem Mol Biol. 2002;83:5973. 8. Furlow JD, Neff ES. A developmental switch induced by thyroid hormone: Xenopus laevis metamorphosis. Trends Endocrinol Metab. 2006;17:3845. 9. Huang Y-H, Tsai M-M, Lin K-H, et al. Thyroid hormone dependent regulation of target genes and their physiological significance. Chan Gung Med J. 2008;31:325333. 10. Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006;116:25712579. 11. Feng X, Jiang Y, Meltzer P, et al. Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray. Mol Endocrinol. 2000;14:947955.
Use for Diagnosis and Treatment The free or total T4 and/or T3 levels are routinely measured in the diagnosis of thyroid diseases, including hyperthyroidism, thyroiditis, and hypothyroidism. Patients with TH resistance are usually identified with elevated levels of free or total T4 and/or T3 in association with normal or slightly elevated thyrotropin [5]. The most common cause is TRβ gene mutations. However, mutations in monocarboxylate transporter 8 responsible for T3 uptake and in selenocysteine insertion sequence binding protein 2 that is required for a translational step of selenium-containing deiodinase transcripts have also been associated with this condition. T3 mimetic eprotirome (KB2115) and sobetirome (GC-1) effectively decrease plasma low-density lipoprotein cholesterol and stimulate bile acid synthesis in humans.
Supplemental Information Available on Companion Website • TRα and TRβ gene structures in the mouse genome and TR isoforms/E-Figure 93A.1 • Pie chart diagram of expression profiling data of 149 upregulated genes from microarray analysis in HepG2-TRα cells treated with 100 nM T3/E-Figure 93A.2 • Human iodothyronine deiodinases and their properties/ETable 93A.1 • List of hepatic genes regulated by T3 determined by microarray analyses/E-Table 93A.2
497
3,30,5-Triiodothyronine Kiyoshi Yamauchi
Abbreviation: T3 Additional names: liothyronine, liothyronin, tresitope IUPAC Name: (2S)-2-amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3,5-diiodo-phenyl]propanoic acid CAS No. 6893-02-3 T3 is an active form of thyroid hormone (TH), which plays an important role in body control, including growth and development, metabolism, body temperature, and heart rate.
Discovery Jack Gross and Rosalind Pitt-Rivers identified T3 in human plasma as a more active component than thyroxine (T4), in 1952 [1]. Rat liver deiodinase 1 was described as the first deiodinase enzyme for THs in 1976 [2].
Structure Structural Features T3 is a derivative of amino acid tyrosine. T3 has one iodine atom in the phenolic ring and two in the tyrosyl ring.
TRα and THRB for TRβ, which are located on 17q11.2 and 3p24.2, respectively, in humans. By alternative splicing and usage of internal ATG as a translational initiation site, these genes produce variable isoforms in rats and mice (E-Figure 93A.1), five of which are T3-binding isoforms: α1, p43, β1, β2, and β3 (Figure 93A.2) [6]. The isoform p43 acts as a TR in the mitochondrial matrix. The others lack TH binding activity due to the replacement of the critical TH binding region in the C-terminal region of TRα1, and act as TR antagonists. These isoforms are differentially expressed, showing isoformspecific physiological roles with some level of redundancy. Variable actions of THs are generated by the diversity of THresponse elements (TREs) (Figure 93A.3) and heterodimeric partners of TRs as well as different isoforms of TRs. The core TREs sequence is the hexanucleotide half-site (A/G)GGT(C/ A/G)A. TRE half-sites are present in pairs: direct repeat, inverted repeat, and everted repeat. Retinoid X receptor (RXR), vitamin D3 receptor (VDR), and peroxisome proliferator-activated receptor (PPAR) are known as heterodimer partners. In mitochondria, the truncated form of TRα1, p43, binds to one of the highly related TREs in the D-loop region.
Properties Molecular formula, C15H12I3NO4; Mr 650.97; physical state: solid, odorless, and tasteless; water solubility: 3.96 mg/l at 37 C.
Synthesis and Release Synthesis Eighty percent of circulating T3 is generated from T4 by deiodinases 1 and 2 (DIO1 and DIO2) in peripheral tissues (ETable 93A.1). These enzymes are selenocysteine-dependent membrane proteins. However, T4 is also converted to various metabolites in addition to T3 by specifc enzymes [3] as shown in Figure 93A.1. Daily production rates of T3 are 48 nmol/ day/70 kg, respectively [4].
Gene and mRNA DIO1 and DIO2 are located on 1p33p32 and 14q24.224.3, respectively.
Receptors Structure and Subtype Nuclear TH receptors (TRs) function as T3-dependent transcription factors [5]. TRs are encoded by two genes: THRA for
Signal Transduction Pathways After T3 binding to TRs on TREs in TH-induced target genes, major conformational changes in the helix 12 in the ligand-binding domain occurs. This induces a coregulator switch from a corepressor complex to a coactivator complex. Major corepressors are nuclear receptor corepressor (N-CoR) and silencing mediator of retinoic acid and TR (SMRT), which can associate with histone deacetylase 3 (HDAC3) to form a complex resulting in a compact state of chromatin via HDAC activity. Coactivators, including steroid receptor coactivators (SRC/p160) family and TR-associated proteins (TRAP), have histone acetyltransferase (HAT) activity or can recruit HATs to create a relaxed state of chromatin. This facilitates the recruitment of general transcription factors and RNA polymerase II. Phosphorylation of TRβ1 at serine 142 by MAPK (ERK1/2) also accelerates the coregulator switch.
Agonists T3 and Triac are more potent agonists than T4. A derivative of Triac, GC-1, is a synthetic TRβ-selective agonist [7]. Tetrabromobisphenol A has weak agonist activity.
Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00217-8 © 2016 Elsevier Inc. All rights reserved.
495
P A R T I I I Lipophilic Hormones in Vertebrates
Figure 93A.1 T3 synthesis and various metabolic pathways of T4.
Figure 93A.2 Mammalian TR subtypes, and their domain structure and expression sites.
Figure 93A.3 Three types of TREs.
Antagonists A derivative of Triac, NH-3, is a synthetic antagonist [7]. Tetrabromobisphenol A shows weak antagonist activity.
Biological Functions Target Cells/Tissues and Functions THs control normal growth and development in bone and central nervous system, and regulate lipids in adipose tissue. THs 496
also increase the metabolic rate in most metabolically active tissues in mammals by increasing absorption of carbohydrates from intestine, protein breakdown in muscle, O2 dissociation from hemoglobin, and O2 consumption [4]. These TH effects can be divided into two mechanistically different actions: genomic actions mediated by nuclear TRs in the nucleus and nongenomic actions that occur at the plasma membrane, in cytoplasm, and at subcellular organelles. T3-regulated hepatic and HepG2 genes, which are determined by microarray analyses, are shown in E-Table 93A.2 and E-Figure 93A.2.
S U B C H A P T E R 9 3 A 3,30 ,5-Triiodothyronine Phenotype in Gene-Modified Animals Mice lacking TRα1 have abnormal heart function and decreased body temperature. Mice lacking both TRα1 and TRα2 have impaired postnatal development and decreased postnatal survival, whereas mice lacking the TRβ gene have mild dysfunction of the pituitarythyroid axis, and a deficit in auditory function and eye development. Knock-in mice harboring a C-terminal frameshifted TRβ have dysfunction of the pituitary-thyroid axis and the nervous system, abnormal regulation of cholesterol, neurological growth retardation, hearing loss, and thyrotoxic skeletal phenotype [5,6]. In an amphibian, transgenic Xenopus laevis overexpressing dominant negative TRα prevents coactivator recruitment. This affects proliferation of the jaw and brain, resorption of the gills and tail, and remodeling of the intestinal tract [8].
Pathophysiological Implications Clinical Implications A close relationship is found between more than 347 family members with TH resistance (Refetoff syndrome) and 124 different mutations in the TRβ gene. Symptoms of this disorder are increased TH with non-suppressible thyrotropin, goiter, short stature, decreased weight, tachycardia, hearing loss, attention deficit hyperactivity disorder, and dyslexia, but most patients are heterozygous and are euthyroid. Mutant proteins act as a dominant negative form of TRβ. In contrast, there have been no reports on TRα mutation in humans [5].
References 1. Gross J, Pitt-Rivers R. The identification of 3:5:30 -L-triiodothyronine in human plasma. Lancet. 1952;1:439441. 2. Visser TJ, Does-Tobe´ I, Docter R, et al. Subcellular localization of a rat liver enzyme converting thyroxine into tri-iodothyronine and possible involvement of essential thiol groups. Biochem J. 1976;157:479482. 3. Wu SY, Green WL, Huang WS, et al. Alternate pathways of thyroid hormone metabolism. Thyroid. 2005;15:943958. 4. Braverman LE, Utiger RD, (eds). Werner and Ingbar’s The Thyroid: A fundamental and clinical text. 7th ed. Philadelphia: Lippincott-Raven; 1996. 5. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31:139170. 6. Flamant F, Samarut J. Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab. 2003;14:8590. 7. Webb P, Nguyen NH, Chiellini G, et al. Design of thyroid hormone receptor antagonists from first principles. J Steroid Biochem Mol Biol. 2002;83:5973. 8. Furlow JD, Neff ES. A developmental switch induced by thyroid hormone: Xenopus laevis metamorphosis. Trends Endocrinol Metab. 2006;17:3845. 9. Huang Y-H, Tsai M-M, Lin K-H, et al. Thyroid hormone dependent regulation of target genes and their physiological significance. Chan Gung Med J. 2008;31:325333. 10. Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006;116:25712579. 11. Feng X, Jiang Y, Meltzer P, et al. Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray. Mol Endocrinol. 2000;14:947955.
Use for Diagnosis and Treatment The free or total T4 and/or T3 levels are routinely measured in the diagnosis of thyroid diseases, including hyperthyroidism, thyroiditis, and hypothyroidism. Patients with TH resistance are usually identified with elevated levels of free or total T4 and/or T3 in association with normal or slightly elevated thyrotropin [5]. The most common cause is TRβ gene mutations. However, mutations in monocarboxylate transporter 8 responsible for T3 uptake and in selenocysteine insertion sequence binding protein 2 that is required for a translational step of selenium-containing deiodinase transcripts have also been associated with this condition. T3 mimetic eprotirome (KB2115) and sobetirome (GC-1) effectively decrease plasma low-density lipoprotein cholesterol and stimulate bile acid synthesis in humans.
Supplemental Information Available on Companion Website • TRα and TRβ gene structures in the mouse genome and TR isoforms/E-Figure 93A.1 • Pie chart diagram of expression profiling data of 149 upregulated genes from microarray analysis in HepG2-TRα cells treated with 100 nM T3/E-Figure 93A.2 • Human iodothyronine deiodinases and their properties/ETable 93A.1 • List of hepatic genes regulated by T3 determined by microarray analyses/E-Table 93A.2
497