CoChat
Sign Up
Cited by 67Thyroid Disorders and TreatmentsThyroid Cancer Diagnosis and TreatmentChemical Analysis and Environmental Impact

The colorful diversity of thyroid hormone metabolites

Open access
Köhrle, Josef·2019·European Thyroid Journal
DOI 10.1159/000497141PMC PMC6587369
Open this paper in CoChat — free accountOpen PDF

Abstract

Since the discovery of L-thyroxine, the main secretory product of the thyroid gland, and its major metabolite T3, which exerts the majority of thyroid hormone action via ligand-dependent modulation of the function of T3 receptors in nuclei, mitochondria, and other subcellular compartments, various other T4-derived endogenous metabolites have been identified in blood and tissues of humans, animals, and early protochordates. This review addresses major historical milestones and experimental findings resulting in the discovery of the key enzymes of thyroid hormone metabolism, the three selenoprotein deiodinases, as well as the decarboxylases and amine oxidases involved in formation and degradation of recently identified endogenous thyroid hormone metabolites, i.e. 3-iodothyronamine and 3-thyroacetic acid. The concerted action of deiodinases 2 and 3 in regulation of local T3 availability is discussed. Special attention is given to the role of the thyromimetic “hot” metabolite 3,5-T2 and the “cool” 3-iodothyronamine, especially after administration of pharmacological doses of these endogenous thyroid hormone metabolites in various animal experimental models. In addition, available information on the biological roles of the two major acetic acid derivatives of thyroid hormones, i.e. Tetrac and Triac, as well as sulfated metabolites of thyroid hormones is reviewed. This review addresses the consequences of the existence of this broad spectrum of endogenous thyroid hormone metabolites, the “thyronome,” beyond the classical thyroid hormone profile comprising T4, T3, and rT3 for appropriate analytical coverage and clinical diagnostics using mass spectrometry versus immunoassays for determination of total and free concentrations of thyroid hormone metabolites in blood and tissues.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1159/000497141

Cites

13 of 13 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Extrathyroidal formation of 3,5-T2 has been supported by studies using radioimmunoassays based on poly- or monoclonal antibodies.

    “Most of these studies were feasible after the development of specific radioimmunoassays, based on poly- or monoclonal antibodies in the Seventies of the last century, and supported extrathyroidal formation of 3,5-T2, which had been previously demonstrated using radioisotope-labeled TH in humans, experimental animal models, and in vitro systems [see recent reviews: (3, 9)].”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [9]

    The sections on 3,5-T2 and its serum concentrations report radioimmunoassays and a later monoclonal-antibody immunoassay; the latter found 3,5-T2 in patients lacking functional thyroid tissue, consistent with extrathyroidal formation. But the paper describes that monoclonal assay as chemiluminescent, not a radioimmunoassay, and treats the proposed site of formation as an assumption rather than an established result of those assays. The supplied copy gives no page numbers for these passages. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Tetrac, a deaminated side chain metabolite of T4, present in human serum at concentrations similar to those of T3, antagonizes T4 (and also T3) actions at the integrin receptor signaling.

    “The T4 metabolite Tetrac, a deaminated side chain metabolite, present in human serum at concentrations similar to those of T3 (3, 9) antagonizes such T4 (and also T3) actions at the integrin receptor signaling.”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [9]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 96

  1. Mackenzie HW. A Case of Myxoedema Treated with Great Benefit by Feeding with Fresh Thyroid Glands. Br Med J. 1892 Oct 29;2(1661):940-1.
  2. Hennessey JV. Historical and Current Per- spective in the Use of Thyroid Extracts for the Treatment of Hypothyroidism. Endocr Pract. 2015 Oct;21(10):1161-70.
  3. de Carvalho GA, Paz-Filho G, Mesa Junior C, Graf H. Management of endocrine dis- ease: Pitfalls on the replacement therapy for primary and central hypothyroidism in adults. Eur J Endocrinol. 2018 Jun;178(6):R231-R244.
  4. Michaelsson LF, Medici BB, la Cour JL, Selmer C, Røder M, Perrild H, et al. Treat- ing Hypothyroidism with Thyrox- ine/Triiodothyronine Combination Thera- py in Denmark: Following Guidelines or Following Trends? Eur Thyroid J. 2015 Sep;4(3):174-80.
  5. Wiersinga WM. Therapy of endocrine dis- ease: T4 + T3 combination therapy: is there a true effect? Eur J Endocrinol. 2017 Dec;177(6):R287-R296.
  6. Gross J, Pitt-Rivers R. 3:5:3′ - triiodothyronine. 1. Isolation from thyroid gland and synthesis. Biochem J. 1953 Mar;53(4):645-50.
  7. Gross J, Pitt-Rivers R. 3:5:3′- triiodothyronine. 2. Physiological activity. Biochem J. 1953 Mar;53(4):652-7.
  8. Vella KR, Hollenberg AN. The actions of thyroid hormone signaling in the nucleus. Mol Cell Endocrinol. 2017 Dec 15;458:127- 135.
  9. Zimmermann MB. Research on iodine de- ficiency and goiter in the 19th and early 20th centuries. J Nutr. 2008 Nov;138(11):2060-3.
  10. Kendall EC. The Isolation in Crystalline Form of the Compound Containing Iodin, Which Occurs in the Thyroid. Its Chemical Nature and Physiologic Activity. JAMA. 1915;64(25):2042-3.
  11. Hird F Jr, Trikojus VM. Paper partition chromatography with thyroxine and ana- logues. Aust J Sci. 1948 Jun;10(6):185-7.
  12. Barker SB, Klitgaard HM. Metabolism of tissues excised from thyroxine-injected rats. Am J Physiol. 1952 Jul;170(1):81-6.
  13. Gudernatsch JF. Feeding experiments on tadpoles. Arch Entwicklungsmech Organ 1912;35(3):457-83.
  14. Braverman LE, Ingbar SH, Sterling K. Con- version of thyroxine (T4) to triiodothyro- nine (T3) in athyreotic human subjects. J Clin Invest. 1970 May;49(5):855-64.
  15. Koerner D, Schwartz HL, Surks MI, Op- penheimer JH. Binding of selected iodothy- ronine analogues to receptor sites of isolat- ed rat hepatic nuclei. High correlation be- tween structural requirements for nuclear binding and biological activity. J Biol Chem. 1975 Aug;250(16):6417-23.
  16. Sterling K, Milch PO, Brenner MA, Lazarus JH. Thyroid hormone action: the mito- chondrial pathway. Science. 1977 Sep;197(4307):996-9.
  17. Wrutniak-Cabello C, Casas F, Cabello G. Mitochondrial T3 receptor and targets. Mol Cell Endocrinol. 2017 Dec;458:112-20.
  18. Sap J, Muñoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, et al. The c-erb-A pro- tein is a high-affinity receptor for thyroid hormone. Nature. 1986 Dec;324(6098):635-40.
  19. Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, Evans RM. The c-erb-A gene encodes a thyroid hormone receptor. Nature. 1986 Dec;324(6098):641-6.
  20. Köhrle J. Thyroid Hormones and Deriva- tives: Endogenous Thyroid Hormones and Their Targets. Methods Mol Biol. 2018;1801:85-104.
  21. Louzada RA, Carvalho DP. Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites. Front Endocrinol (Lausanne). 2018 Jul 19;9:394.
  22. Moreno M, Giacco A, Di Munno C, Goglia F. Direct and rapid effects of 3,5-diiodo-L- thyronine (T2). Mol Cell Endocrinol. 2017 Dec;458:121-6.
  23. Jonas W, Lietzow J, Wohlgemuth F, Hoefig CS, Wiedmer P, Schweizer U, et al. 3,5- Diiodo-L-thyronine (3,5-t2) exerts thyro- mimetic effects on hypothalamus-pituitary- thyroid axis, body composition, and energy metabolism in male diet-induced obese mice. Endocrinology. 2015 Jan;156(1):389- 99.
  24. Baur A, Bauer K, Jarry H, Köhrle J. 3,5- diiodo-L-thyronine stimulates type 1 5'deiodinase activity in rat anterior pitui- taries in vivo and in reaggregate cultures and GH3 cells in vitro. Endocrinology. 1997 Aug;138(8):3242-8.
  25. Scanlan TS, Suchland KL, Hart ME, Chiel- lini G, Huang Y, Kruzich PJ, et al. 3- Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hor- mone. Nat Med. 2004 Jun;10(6):638-42.
  26. Hoefig CS, Wuensch T, Rijntjes E, Lehmphul I, Daniel H, Schweizer U, et al. Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue. Endocri- nology. 2015 Nov;156(11):4356-64.
  27. Hoefig CS, Zucchi R, Köhrle J. Thyrona- mines and Derivatives: Physiological Rele- vance, Pharmacological Actions, and Fu- ture Research Directions. Thyroid. 2016 Dec;26(12):1656-1673.
  28. Baumann E. Ueber das normale Vork- ommen von Jod im Thierkörper. Z Physiol Chem. 1895;21:319-30.
  29. Kurmann AA, Serra M, Hawkins F, Rankin SA, Mori M, Astapova I, et al. Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells. Cell Stem Cell. 2015 Nov;17(5):527-42.
  30. Davies TF. Is thyroid transplantation on the distant horizon? Thyroid. 2013 Feb;23(2):139-41.
  31. Nilsson M, Fagman H. Development of the thyroid gland. Development. 2017 Jun;144(12):2123-2140.
  32. Ramsden DB, Lawson AM, Raw PJ, Hof- fenberg R. The identification of 3,3′, 5,5′,- tetraiodothyroformic acid within the rat liver. Biochem J. 1974 Oct;143(1):47-50.
  33. Carvalho DP, Dupuy C. Thyroid hormone biosynthesis and release. Mol Cell Endo- crinol. 2017 Dec;458:6-15.
  34. Meinhold H, Gramm HJ, Meissner W, Zimmermann J, Schwander J, Dennhardt R, et al. Elevated serum diiodotyrosine (DIT) in severe infections and sepsis: DIT, a possible new marker of leukocyte activity. J Clin Endocrinol Metab. 1991 Apr;72(4):945-53.
  35. Klebanoff SJ, Green WL. Degradation of thyroid hormones by phagocytosing hu- man leukocytes. J Clin Invest. 1973 Jan;52(1):60-72.
  36. Chopra IJ. A radioimmunoassay for meas- urement of 3,3′,5′-triiodothyronine (re- verse T3). J Clin Invest. 1974 Sep;54(3):583-92.
  37. Ködding R, Hesch RD. L-3', 5'- diiodothyronine in human serum. Lancet. 1978 Nov;2(8098):1049.
  38. Wu SY, Polk DH, Chen WL, Fisher DA, Huang WS, Yee B. A 3,3′-diiodothyronine sulfate cross-reactive compound in serum from pregnant women. J Clin Endocrinol Metab. 1994 Jun;78(6):1505-9.
  39. Köhrle J. Thyroid hormone deiodinases -a selenoenzyme family acting as gate keepers to thyroid hormone action. Acta Med Aus- triaca. 1996;23(1-2):17-30.
  40. Manna D, Mugesh G. Regioselective de- iodination of thyroxine by iodothyronine deiodinase mimics: an unusual mechanistic pathway involving cooperative chalcogen and halogen bonding. J Am Chem Soc. 2012 Mar;134(9):4269-79.
  41. Manna D, Mondal S, Mugesh G. Halogen bonding controls the regioselectivity of the deiodination of thyroid hormones and their sulfate analogues. Chemistry. 2015 Feb;21(6):2409-16.
  42. Schweizer U, Schlicker C, Braun D, Köhrle J, Steegborn C. Crystal structure of mam- malian selenocysteine-dependent iodothy- ronine deiodinase suggests a peroxiredox- in-like catalytic mechanism. Proc Natl Acad Sci USA. 2014 Jul;111(29):10526-31.
  43. Köhrle J. Iodothyronine deiodinases. Methods Enzymol. 2002;347:125-67.
  44. Goto K, Sonoda D, Shimada K, Sase S, Ka- washima T. Modeling of the 5′- deiodination of thyroxine by iodothyronine deiodinase: chemical corroboration of a se- lenenyl iodide intermediate. Angew Chem Int Ed Engl. 2010;49(3):545-7.
  45. Köhrle J, Jakob F, Contempré B, Dumont JE. Selenium, the thyroid, and the endo- crine system. Endocr Rev. 2005 Dec;26(7):944-84.
  46. Fortino M, Marino T, Russo N, Sicilia E. A DFT investigation of a bulky biomimetic model catalyzing the 5′-outer ring de- iodination of thyroxine. J Mol Model. 2016 Dec;22(12):287.
  47. Doerge DR, Takazawa RS. Mechanism of thyroid peroxidase inhibition by eth- ylenethiourea. Chem Res Toxicol. 1990 Mar-Apr;3(2):98-101.
  48. Valderrama B, Ayala M, Vazquez-Duhalt R. Suicide inactivation of peroxidases and the challenge of engineering more robust enzymes. Chem Biol. 2002 May;9(5):555- 65.
  49. Horst C, Rokos H, Seitz HJ. Rapid stimula- tion of hepatic oxygen consumption by 3,5- di-iodo-L-thyronine. Biochem J. 1989 Aug;261(3):945-50.
  50. Moreno M, Lombardi A, Beneduce L, Sil- vestri E, Pinna G, Goglia F, et al. Are the ef- fects of T3 on resting metabolic rate in eu- thyroid rats entirely caused by T3 itself? Endocrinology. 2002 Feb;143(2):504-10.
  51. Goglia F. Biological effects of 3,5- diiodothyronine (T2). Biochemistry (Mosc). 2005 Feb;70(2):164-72.
  52. Leonard JL, Koehrle J. Chapter 8: Intracel- lular Pathways of Iodothyronine Metabo- lism. In: Braverman LE, Utiger RD, editors. Werner and Ingbar's The Thyroid: a fun- damental and clinical text. 7th ed. Phila- delphia, London: Lippincott Williams & Wilkins; 1996. pp. 125-61.
  53. Farwell AP, Dubord-Tomasetti SA, Pie- trzykowski AZ, Stachelek SJ, Leonard JL. Regulation of cerebellar neuronal migra- tion and neurite outgrowth by thyroxine and 3,3′,5′-triiodothyronine. Brain Res Dev Brain Res. 2005 Jan;154(1):121-35.
  54. Deng H, Hu H, Fang Y. Multiple tyrosine metabolites are GPR35 agonists. Sci Rep. 2012;2(373):373.
  55. Ambrosio R, De Stefano MA, Di Girolamo D, Salvatore D. Thyroid hormone signaling and deiodinase actions in muscle stem/progenitor cells. Mol Cell Endocrinol. 2017 Dec 25;459:79-83.
  56. Miro C, Ambrosio R, De Stefano MA, Di Girolamo D, Di Cicco E, Cicatiello AG, et al. The Concerted Action of Type 2 and Type 3 Deiodinases Regulates the Cell Cy- cle and Survival of Basal Cell Carcinoma Cells. Thyroid. 2017 Apr;27(4):567-76.
  57. Hüfner M, Grussendorf M, Lorenz U, Knöpfle M. 3,3′,5′-Triiodothyronine (Re- verse T3) in amniotic fluid and cord serum. Eur J Pediatr. 1977 Jul;125(3):213-7.
  58. Cettour-Rose P, Visser TJ, Burger AG, Rohner-Jeanrenaud F. Inhibition of pitui- tary type 2 deiodinase by reverse triiodo- thyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypo- thyroid rats. Eur J Endocrinol. 2005 Sep;153(3):429-34.
  59. Goto-Inoue N, Sato T, Morisasa M, Kashiwagi A, Kashiwagi K, Sugiura Y, et al. Utilizing mass spectrometry imaging to map the thyroid hormones triiodothyro- nine and thyroxine in Xenopus tropicalis tadpoles. Anal Bioanal Chem. 2018 Feb;410(4):1333-40.
  60. Darras VM, Houbrechts AM, Van Herck SL. Intracellular thyroid hormone metabo- lism as a local regulator of nuclear thyroid hormone receptor-mediated impact on vertebrate development. Biochim Biophys Acta. 2015 Feb;1849(2):130-41.
  61. Woods C, Tomlinson JW. The Dehydro- genase Hypothesis. Adv Exp Med Biol. 2015;872:353-80.
  62. Domingues JT, Cattani D, Cesconetto PA, Nascimento de Almeida BA, Pierozan P, Dos Santos K, et al. Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: insight on signaling mechanisms. Mol Cell Endo- crinol. 2018 Jul;470:281-94.
  63. Hercbergs A, Mousa SA, Davis PJ. Nonthy- roidal Illness Syndrome and Thyroid Hor- mone Actions at Integrin αvβ3. J Clin En- docrinol Metab. 2018 Apr;103(4):1291-5.
  64. C R Hebd Seances Acad Sci. 1955 Jan;240(2):251-3.
  65. Roche J, Michel R, Nunez U, Wolf W. Two new hormonal constituents of the thyroid gland: 3, 3'-diiodothyronine and 3, 3', 5'- triiodothyronine [in French]. Biochim Bio- phys Acta. 1955 Sep;18(1):149-50.
  66. Chopra IJ. Chapter 7: Nature, source and relative significance of circulating thyroid hormones. In: Braverman LE, Utiger RD, editors. Werner and Ingbar's The Thyroid: a fundamental and clinical text. 7th ed. Philadelphia, London: Lippincott Williams & Wilkins; 1996. pp. 111-24.
  67. Schmidt RL, LoPresti JS, McDermott MT, Zick SM, Straseski JA. Does Reverse Triio- dothyronine Testing Have Clinical Utility? An Analysis of Practice Variation Based on Order Data from a National Reference La- boratory. Thyroid. 2018 Jul;28(7):842-8.
  68. Lehmphul I, Brabant G, Wallaschofski H, Ruchala M, Strasburger CJ, Köhrle J, et al. Detection of 3,5-diiodothyronine in sera of patients with altered thyroid status using a new monoclonal antibody-based chemilu- minescence immunoassay. Thyroid. 2014 Sep;24(9):1350-60.
  69. Pietzner M, Lehmphul I, Friedrich N, Schurmann C, Ittermann T, Dörr M, et al. Translating pharmacological findings from hypothyroid rodents to euthyroid humans: is there a functional role of endogenous 3,5-T2? Thyroid. 2015 Feb;25(2):188-97.
  70. Massolt ET, van der Windt M, Korevaar TI, Kam BL, Burger JW, Franssen GJ, et al. Thyroid hormone and its metabolites in re- lation to quality of life in patients treated for differentiated thyroid cancer. Clin En- docrinol (Oxf). 2016 Nov;85(5):781-8.
  71. Hoefig CS, Köhrle J, Brabant G, Dixit K, Yap B, Strasburger CJ, et al. Evidence for extrathyroidal formation of 3- iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay. J Clin Endocrinol Metab. 2011 Jun;96(6):1864-72.
  72. Engler D, Burger AG. The deiodination of the iodothyronines and of their derivatives in man. Endocr Rev. 1984 Spring;5(2):151- 84.
  73. Ramsden DB, Raw PJ, Carter PJ, Hoffen- berg R. Estimation of tetraiodothyroacetate in human serum. Proc R Soc Med. 1975 Feb;68(2):69-70.
  74. Groeneweg S, Peeters RP, Visser TJ, Visser WE. Triiodothyroacetic acid in health and disease. J Endocrinol. 2017 Aug;234(2):R99-R121.
  75. Heinen E, Basler M, Herrmann J, Hafner D, Krüskemper HL. Enzyme kinetic and substrate-binding studies of the thyroxine to 3,5,3′-triiodothyronine converting en- zyme in the rat liver microsomal fraction. Endocrinology. 1980 Oct;107(4):1198-204.
  76. LoPresti JS, Anderson KP, Nicoloff JT. Does a hidden pool of reverse triiodothy- ronine (rT3) production contribute to total thyroxine (T4) disposal in high T4 states in man. J Clin Endocrinol Metab. 1990 May;70(5):1479-84.
  77. Köhrle J. [Transfer and metabolism of thy- roid gland hormones in the placenta]. Acta Med Austriaca. 1997;24(4):138-43.
  78. Segal AW, Garcia RC, Harper AM, Banga JP. Iodination by stimulated human neu- trophils. Studies on its stoichiometry, sub- cellular localization and relevance to mi- crobial killing. Biochem J. 1983 Jan;210(1):215-25.
  79. van der Spek AH, Fliers E, Boelen A. Thy- roid hormone metabolism in innate im- mune cells. J Endocrinol. 2017 Feb;232(2):R67-R81.
  80. Mitchell AM, Manley SW, Morris JC, Pow- ell KA, Bergert ER, Mortimer RH. Sodium iodide symporter (NIS) gene expression in human placenta. Placenta. 2001 Feb- Mar;22(2-3):256-8.
  81. Gomes-Lima C, Burman KD. Reverse T3 or perverse T3? Still puzzling after 40 years. Cleve Clin J Med. 2018 Jun;85(6):450-455.
  82. Akturk M, Oruc AS, Danisman N, Erkek S, Buyukkagnici U, Unlu E, et al. Na+/I- symporter and type 3 iodothyronine de- iodinase gene expression in amniotic membrane and placenta and its relation- ship to maternal thyroid hormones. Biol Trace Elem Res. 2013 Sep;154(3):338-44.
  83. Huang SA. Physiology and pathophysiolo- gy of type 3 deiodinase in humans. Thy- roid. 2005 Aug;15(8):875-81.
  84. Dentice M, Antonini D, Salvatore D. Type 3 deiodinase and solid tumors: an intri- guing pair. Expert Opin Ther Targets. 2013 Nov;17(11):1369-79.
  85. Nishimura K, Takeda M, Yamashita JK, Shiojima I, Toyoda N. Type 3 iodothyro- nine deiodinase is expressed in human in- duced pluripotent stem cell derived cardi- omyocytes. Life Sci. 2018 Jun;203:276-81.
  86. Renko K, Schäche S, Hoefig CS, Welsink T, Schwiebert C, Braun D, et al. An Improved Nonradioactive Screening Method Identi- fies Genistein and Xanthohumol as Potent Inhibitors of Iodothyronine Deiodinases. Thyroid. 2015 Aug;25(8):962-8.
  87. Senese R, de Lange P, Petito G, Moreno M, Goglia F, Lanni A. 3,5-Diiodothyronine: A Novel Thyroid Hormone Metabolite and Potent Modulator of Energy Metabolism. Front Endocrinol (Lausanne). 2018 Jul;9:427. 142.Silvestri E, Lombardi A, Coppola M, Gen- tile A, Cioffi F, Senese R, et al. Differential Effects of 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine On Mitochon- drial Respiratory Pathways in Liver from Hypothyroid Rats. Cell Physiol Biochem. 2018;47(6):2471-83. 143.
  88. Antonelli A, Fallahi P, Ferrari SM, Di Do- menicantonio A, Moreno M, Lanni A, et al. 3,5-diiodo-L-thyronine increases resting metabolic rate and reduces body weight without undesirable side effects. J Biol Reg- ul Homeost Agents. 2011 Oct- Dec;25(4):655-60. 144.van der Valk F, Hassing C, Visser M, Thakkar P, Mohanan A, Pathak K, et al. The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized con- trolled trial. PLoS One. 2014 Feb;9(2):e86890. 145.
  89. Cioffi F, Zambad SP, Chhipa L, Senese R, Busiello RA, Tuli D, et al. TRC150094, a novel functional analog of iodothyronines, reduces adiposity by increasing energy ex- penditure and fatty acid oxidation in rats receiving a high-fat diet. FASEB J. 2010 Sep;24(9):3451-61. 146.Goldberg IJ, Huang LS, Huggins LA, Yu S, Nagareddy PR, Scanlan TS, et al. Thyroid hormone reduces cholesterol via a non- LDL receptor-mediated pathway. Endocri- nology. 2012 Nov;153(11):5143-9. 147.Vatner DF, Snikeris J, Popov V, Perry RJ, Rahimi Y, Samuel VT. 3,5 Diiodo-L- Thyronine (T2) Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats. PLoS One. 2015 Oct;10(10):e0140837. 148.
  90. Angelin B, Kristensen JD, Eriksson M, Carlsson B, Klein I, Olsson AG, et al. Re- ductions in serum levels of LDL cholester- ol, apolipoprotein B, triglycerides and lipo- protein(a) in hypercholesterolaemic pa- tients treated with the liver-selective thy- roid hormone receptor agonist eprotirome. J Intern Med. 2015 Mar;277(3):331-42. 149.Kersseboom S, van Gucht AL, van Mullem A, Brigante G, Farina S, Carlsson B, et al. Role of the Bile Acid Transporter SLC10A1 in Liver Targeting of the Lipid-Lowering Thyroid Hormone Analog Eprotirome. Endocrinology. 2017 Oct;158(10):3307-18. 150.Sinha RA, Singh BK, Yen PM. Direct ef- fects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018 May;14(5):259-269. 151.Sacripanti G, Nguyen NM, Lorenzini L, Frascarelli S, Saba A, Zucchi R, et al. 3,5- Diiodo-l-Thyronine Increases Glucose Consumption in Cardiomyoblasts Without Affecting the Contractile Performance in Rat Heart. Front Endocrinol (Lausanne). 2018 May;9:282. 152.Moreno M, Silvestri E, De Matteis R, de Lange P, Lombardi A, Glinni D, et al. 3,5- Diiodo-L-thyronine prevents high-fat-diet- induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations. FASEB J. 2011 Oct;25(10):3312-24. 153.Accorroni A, Saponaro F, Zucchi R. Tissue thyroid hormones and thyronamines. Heart Fail Rev. 2016 Jul;21(4):373-90. 154.
  91. Lanni A, Moreno M, Lombardi A, de Lange P, Silvestri E, Ragni M, et al. 3,5- diiodo-L-thyronine powerfully reduces ad- iposity in rats by increasing the burning of fats. FASEB J. 2005 Sep;19(11):1552-4. 155.Lombardi A, de Lange P, Silvestri E, Busi- ello RA, Lanni A, Goglia F, et al. 3,5- Diiodo-L-thyronine rapidly enhances mi- tochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP- activated protein kinase involvement. Am J Physiol Endocrinol Metab. 2009 Mar;296(3):E497-502. 156.Shang G, Gao P, Zhao Z, Chen Q, Jiang T, Zhang N, et al. 3,5-Diiodo-l-thyronine ameliorates diabetic nephropathy in strep- tozotocin-induced diabetic rats. Biochim Biophys Acta. 2013 May;1832(5):674-84. 157.Pinna G, Brödel O, Visser T, Jeitner A, Grau H, Eravci M, et al. Concentrations of seven iodothyronine metabolites in brain regions and the liver of the adult rat. Endo- crinology. 2002 May;143(5):1789-800. 158.Kinne A, Wittner M, Wirth EK, Hinz KM, Schülein R, Köhrle J, et al. Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3′-Diiodothyronine across the Plasma Membrane. Eur Thyroid J. 2015 Sep;4 Suppl 1:42-50. 159.Hinz KM, Neef D, Rutz C, Furkert J, Köhrle J, Schülein R, et al. Molecular fea- tures of the L-type amino acid transporter 2 determine different import and export profiles for thyroid hormones and amino acids. Mol Cell Endocrinol. 2017 Mar;443:163-74. 160.Eravci M, Pinna G, Meinhold H, Baum- gartner A. Effects of pharmacological and nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain. Endocrinology. 2000 Mar;141(3):1027-40. 161.Pinna G, Broedel O, Eravci M, Stolten- burg-Didinger G, Plueckhan H, Fuxius S, et al. Thyroid hormones in the rat amygdala as common targets for antidepressant drugs, mood stabilizers, and sleep depriva- tion. Biol Psychiatry. 2003 Nov;54(10):1049-59. 162.Broedel O, Eravci M, Fuxius S, Smolarz T, Jeitner A, Grau H, et al. Effects of hyper- and hypothyroidism on thyroid hormone concentrations in regions of the rat brain. Am J Physiol Endocrinol Metab. 2003 Sep;285(3):E470-80. 163.Dietrich JW, Müller P, Schiedat F, Schlö- micher M, Strauch J, Chatzitomaris A, et al. Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling. Eur Thyroid J. 2015 Jun;4(2):129-37. 164.Langouche L, Lehmphul I, Perre SV, Köhrle J, Van den Berghe G. Circulating 3- T1AM and 3,5-T2 in Critically Ill Patients: A Cross-Sectional Observational Study. Thyroid. 2016 Dec;26(12):1674-80. 165.Pietzner M, Homuth G, Budde K, Lehmphul I, Völker U, Völzke H, et al. Urine Metabolomics by (1)H-NMR Spec- troscopy Indicates Associations between Serum 3,5-T2 Concentrations and Inter- mediary Metabolism in Euthyroid Hu- mans. Eur Thyroid J. 2015 Sep;4 Suppl 1:92-100. 166.Friedrich N, Pietzner M, Cannet C, Thuesen BH, Hansen T, Wallaschofski H, et al. Urinary metabolomics reveals glyce- mic and coffee associated signatures of thy- roid function in two population-based co- horts. PLoS One. 2017 Mar;12(3):e0173078. 167.Pietzner M, Kacprowski T, Friedrich N. Empowering thyroid hormone research in human subjects using OMICs technologies. J Endocrinol. 2018 Jul;238(1):R13-R29. 168.Orozco A, Lazcano I, Hernández-Puga G, Olvera A. Non-mammalian models reveal the role of alternative ligands for thyroid hormone receptors. Mol Cell Endocrinol. 2017 Dec;459:59-63. 169.Olvera A, Martyniuk CJ, Buisine N, Jimé- nez-Jacinto V, Sanchez-Flores A, Sachs LM, et al. Differential transcriptome regu- lation by 3,5-T2 and 3′,3,5-T3 in brain and liver uncovers novel roles for thyroid hor- mones in tilapia. Sci Rep. 2017 Nov;7(1):15043. 170.Pinna G, Meinhold H, Hiedra L, Thoma R, Hoell T, Gräf KJ, et al. Elevated 3,5- diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors. J Clin Endocrinol Metab. 1997 May;82(5):1535-42. 171.
  92. Iannucci LF, Cioffi F, Senese R, Goglia F, Lanni A, Yen PM, et al. Metabolomic anal- ysis shows differential hepatic effects of T2 and T3 in rats after short-term feeding with high fat diet. Sci Rep. 2017 May;7(1):2023. 172.
  93. Harder L, Schanze N, Sarsenbayeva A, Ku- gel F, Köhrle J, Schomburg L, et al. In vivo Effects of Repeated Thyronamine Admin- istration in Male C57BL/6J Mice. Eur Thy- roid J. 2018 Jan;7(1):3-12. 173.
  94. Gachkar S, Oelkrug R, Martinez-Sanchez N, Rial-Pensado E, Warner A, Hoefig CS, et al. 3-Iodothyronamine Induces Tail Vas- odilation Through Central Action in Male Mice. Endocrinology. 2017 Jun;158(6):1977-84. 174.Hoefig CS, Jacobi SF, Warner A, Harder L, Schanze N, Vennström B, et al. 3- Iodothyroacetic acid lacks thermoregulato- ry and cardiovascular effects in vivo. Br J Pharmacol. 2015 Jul;172(13):3426-33. 175.
  95. Köhrle J, Biebermann H. 3- iodothyronamine -a thyroid hormone me- tabolite with distinct target profiles and mode of action. Endocr Rev. 2019 Jan 10. doi: 10.1210/er.2018-00182. 176.Dratman MB. On the mechanism of action of thyroxin, an amino acid analog of tyro- sine. J Theor Biol. 1974 Jul;46(1):255-70. 177.Hoefig CS, Renko K, Piehl S, Scanlan TS, Bertoldi M, Opladen T, et al. Does the ar- omatic L-amino acid decarboxylase con- tribute to thyronamine biosynthesis? Mol Cell Endocrinol. 2012 Feb;349(2):195-201. 178.Roy G, Placzek E, Scanlan TS. ApoB-100- containing lipoproteins are major carriers of 3-iodothyronamine in circulation. J Biol Chem. 2012 Jan;287(3):1790-800. 179.Braulke LJ, Klingenspor M, DeBarber A, Tobias SC, Grandy DK, Scanlan TS, et al. 3-Iodothyronamine: a novel hormone con- trolling the balance between glucose and li- pid utilisation. J Comp Physiol B. 2008 Feb;178(2):167-77. 180.Doyle KP, Suchland KL, Ciesielski TM, Lessov NS, Grandy DK, Scanlan TS, et al. Novel thyroxine derivatives, thyronamine and 3-iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury. Stroke. 2007 Sep;38(9):2569-76. 181.Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW, et al. Probing cell type-specific functions of Gi in vivo identi- fies GPCR regulators of insulin secretion. J Clin Invest. 2007 Dec;117(12):4034-43. 182.Klieverik LP, Foppen E, Ackermans MT, Serlie MJ, Sauerwein HP, Scanlan TS, et al. Central effects of thyronamines on glucose metabolism in rats. J Endocrinol. 2009 Jun;201(3):377-86. 183.Dhillo WS, Bewick GA, White NE, Gardi- ner JV, Thompson EL, Bataveljic A, et al. The thyroid hormone derivative 3- iodothyronamine increases food intake in rodents. Diabetes Obes Metab. 2009 Mar;11(3):251-60. 184.Frascarelli S, Ghelardoni S, Chiellini G, Galli E, Ronca F, Scanlan TS, et al. Cardio- protective effect of 3-iodothyronamine in perfused rat heart subjected to ischemia and reperfusion. Cardiovasc Drugs Ther. 2011 Aug;25(4):307-13. 185.Venditti P, Napolitano G, Di Stefano L, Chiellini G, Zucchi R, Scanlan TS, et al. Ef- fects of the thyroid hormone derivatives 3- iodothyronamine and thyronamine on rat liver oxidative capacity. Mol Cell Endo- crinol. 2011 Jul;341(1-2):55-62. 186.Haviland JA, Reiland H, Butz DE, Tonelli M, Porter WP, Zucchi R, et al. NMR-based metabolomics and breath studies show li- pid and protein catabolism during low dose chronic T(1)AM treatment. Obesity (Silver Spring). 2013 Dec;21(12):2538-44. 187.Selen Alpergin ES, Bolandnazar Z, Sabatini M, Rogowski M, Chiellini G, Zucchi R, et al. Metabolic profiling reveals reprogram- ming of lipid metabolic pathways in treat- ment of polycystic ovary syndrome with 3- iodothyronamine. Physiol Rep. 2017 Jan;5(1):e13097. 188.Assadi-Porter FM, Reiland H, Sabatini M, Lorenzini L, Carnicelli V, Rogowski M, et al. Metabolic Reprogramming by 3- Iodothyronamine (T1AM): A New Per- spective to Reverse Obesity through Co- Regulation of Sirtuin 4 and 6 Expression. Int J Mol Sci. 2018 May;19(5):E1535. 189.Manni ME, De Siena G, Saba A, Marchini M, Dicembrini I, Bigagli E, et al. 3- Iodothyronamine: a modulator of the hy- pothalamus-pancreas-thyroid axes in mice. Br J Pharmacol. 2012 May;166(2):650-8. 190.Dinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, et al. 3- iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signal- ing. J Mol Endocrinol. 2015 Jun;54(3):205- 16. 191.Lehmphul I, Hoefig CS, Köhrle J. 3- Iodothyronamine reduces insulin secretion in vitro via a mitochondrial mechanism. Mol Cell Endocrinol. 2018 Jan;460:219-28. 192.Laurino A, Raimondi L. Commentary: Torpor: The Rise and Fall of 3- Monoiodothyronamine from Brain to Gut- From Gut to Brain? Front Endocrinol (Lausanne). 2017 Aug;8:206. 193.Rutigliano G, Zucchi R. Cardiac actions of thyroid hormone metabolites. Mol Cell Endocrinol. 2017 Dec;458:76-81. 194. · DOI
  96. Jonklaas J, Sathasivam A, Wang H, Gu J, Burman KD, Soldin SJ. Total and free thy- roxine and triiodothyronine: measurement discrepancies, particularly in inpatients. Clin Biochem. 2014 Sep;47(13-14):1272-8. 223.De Grande LA, Van Uytfanghe K, Reynders D, Das B, Faix JD, MacKenzie F, et al.; IFCC Committee for Standardization of Thyroid Function Tests (C-STFT). Standardization of Free Thyroxine Meas- urements Allows the Adoption of a More Uniform Reference Interval. Clin Chem. 2017 Oct;63(10):1642-52. 224.Richards KH, Schanze N, Monk R, Rijntjes E, Rathmann D, Köhrle J. A validated LC- MS/MS method for cellular thyroid hor- mone metabolism: Uptake and turnover of mono-iodinated thyroid hormone metabo- lites by PCCL3 thyrocytes. PLoS One. 2017 Aug;12(8):e0183482. 225.Richards K, Rijntjes E, Rathmann D, Köhrle J. Avoiding the pitfalls when quan- tifying thyroid hormones and their me- tabolites using mass spectrometric meth- ods: The role of quality assurance. Mol Cell Endocrinol. 2017 Dec;458:44-56. 226.Ruggenthaler M, Grass J, Schuh W, Huber CG, Reischl RJ. Levothyroxine sodium re- visited: A wholistic structural elucidation approach of new impurities via HPLC- HRMS/MS, on-line H/D exchange, NMR spectroscopy and chemical synthesis. J Pharm Biomed Anal. 2017 Feb;135:140-52. 227.Neu V, Bielow C, Gostomski I, Wintringer R, Braun R, Reinert K, et al. Rapid and comprehensive impurity profiling of syn- thetic thyroxine by ultrahigh-performance liquid chromatography-high-resolution mass spectrometry. Anal Chem. 2013 Mar;85(6):3309-17

Cited by

Sorted by citations

Authors
Köhrle, J.
Affiliations
Humboldt-Universität zu Berlin (DE)
Corresponding author
Köhrle, Josef
ORCID
Köhrle, Josef
Venue
European Thyroid Journal
Publisher
Bioscientifica
Published
2019-05-21
Volume
8
Issue
3
Pages
115-129
ISSN
  • 2235-0640 (ISSN-L)
  • 2235-0802
DOI
10.1159/000497141
PMC
PMC6587369
OpenAlex
W2946272758
Cited by
67
References
13
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 15 · 2021: 10 · 2020: 15 · 2019: 5 · 2018: 1
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
www.karger.com/Services/SiteLicenses (vor, 2464 d)
Locations
  • European Thyroid Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Chemical Analysis and Environmental Impact
Keywords
thyroid hormone metabolites, deiodinases, 3-iodothyronamine, tetrac, triac, T3 receptor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review