Skip to main content
SpringerLink
Log in

The isolation of thyroxine (T4), the discovery of 3,5,3’-triiodothyronine (T3), and the identification of the deiodinases that generate T3 from T4: An historical review

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. J. Lindholm, P. Laurberg, Hypothyroidism and thyroid substitution: historical aspects. J. Thyroid Res. 2011, 1–10 (2011)

    Article  Google Scholar 

  2. G.R. Murray, Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of sheep. Brit. Med. J. 2, 786–797 (1891)

    Article  Google Scholar 

  3. E. C. Kendall, Cortisone (Charles Scribner’s Sons, New York, 1971).

  4. E. Baumann, [Ueber das normale Vorkommen von Jod im Thierkorper]. Z. Physiol. Chem. 21, 319–330 (1896).

  5. H. Clapesattle, The Doctors Mayo (Mayo Clinic, Rochester, Minnesota, 1969).

  6. T Rooke. The Quest for Cortisone (Michigan State University Press, Lansing Michigan, (2012).

    Google Scholar 

  7. E.C. Kendall, The isolation in crystalline form of the compound containing iodine which occurs in the thyroid gland. J. Am. Med. Assoc. 64, 2042–2043 (1915)

    Article  CAS  Google Scholar 

  8. C.R. Harington, Chemistry of thyroxine. I. Isolation of thyroxine from the thyroid gland. Biochem. J. 20, 293–299 (1926)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. C.R. Harington, Chemistry of thyroxine. II. Constitution and synthesis of desiodothyroxine. Biochem. J. 20, 300–313 (1926)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. J.H. Means, Therapeutics of the thyroid. J. Am. Med. Assoc. 105, 24–28 (1935)

    Article  CAS  Google Scholar 

  11. C.R. Harington, Bichemical basis of thyroid function. Lancet 225, 1261–1267 (1935)

    Article  Google Scholar 

  12. C.R. Harington, Croonian lecture: thyroxine: its biosynthesis and its immunochemistry. Proc. R. Soc. Lond. Ser. B 132, 223–238 (1944)

    Article  CAS  Google Scholar 

  13. A. Taurog, I.L. Chaikoff, The nature of the circulating thyroid hormone. J. Biol. Chem. 176, 639–656 (1948)

    CAS  PubMed  Google Scholar 

  14. J.C. Laidlaw, Nature of the circulating thyroid hormone. Nature 164, 927–928 (1949)

    Article  CAS  PubMed  Google Scholar 

  15. J. Gross et al. Presence of iodinated amino acids in unhydrolyzed thyroid and plasma. Science 111, 605–608 (1950)

    Article  CAS  PubMed  Google Scholar 

  16. F.D. Hart, N.F. Maclagan, Oral thyroxine in the treatment of myxoedema. Brit. Med. J. 1(4652), 512–518 (1950)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. S.C. Kaufman, Thyroid hormone use: trends in the United States from 1960 through 1988. Thyroid 1, 285–291 (1991)

    Article  CAS  PubMed  Google Scholar 

  18. J. Gross, R. Pitt-Rivers, The identification of 3,5,3’L-triiodothyronine in human plasma. Lancet 259, 439–441 (1952)

    Article  Google Scholar 

  19. J. Gross, R. Pitt-Rivers, 3:5:3’-triiodothyronine. 1. Isolation from thyroid gland and synthesis. Biochem. J. 53, 645–652 (1953)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. J. Roche, S. Lissitsky, R. Michel, Sur la presence de triiodothyronine dans la thyroglobuline. C. R. Acad. Sci. 234, 1228–1230 (1952)

    CAS  Google Scholar 

  21. J. Gross, R. Pitt-Rivers, W.R. Trotter, Effect of 3,5,3’-L-triiodothyronine in myxoedema. Lancet 259, 1044–1045 (1952)

    Article  Google Scholar 

  22. J. Gross, R. Pitt-Rivers, Physiological activity of 3:5:3’-L-Triiodothyronine. Lancet 259, 593–594 (1952)

    Article  Google Scholar 

  23. J. Gross, R. Pitt-Rivers, 3:5:3’-triiodothyronine. 2. Physiological activity. Biochem. J. 53, 652–656 (1953)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. R. Pitt-Rivers, J.B. Stanbury, B. Rapp, Conversion of thyroxine to 3,5,3’-triiodothyronine in vivo. J. Clin. Endocrinol. Metab. 15, 616–620 (1955)

    Article  CAS  PubMed  Google Scholar 

  25. W.E. Lassiter, J.B. Stanbury, In vivo conversion of thyroxine to 3,5,3’ triiodothyronine. J. Clin. Endocrinol. Metab. 18, 903–906 (1958)

    Article  CAS  PubMed  Google Scholar 

  26. E.C. Albright, F.C. Larson, R.H. Tust, In vitro conversion of thyroxine to triiodothyronine by kidney slices. Proc. Soc. Expt. Biol. Med. 86, 137–140 (1954)

    Article  CAS  Google Scholar 

  27. E.C. Albright, F.C. Larsen, Metabolism of L-thyroxine by human tissue slices. J. Clin. Invest. 38, 1899–1903 (1959)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. S.H. Ingbar, V.A. Galton, Thyroid. Ann. Rev. Physiol. 25, 361–380 (1963)

    Article  CAS  Google Scholar 

  29. L.E. Braverman, S.H. Ingbar, K. Sterling, Conversion of thyroxine to triiodothyronine in athyreotic human subjects. J. Clin. Invest. 49, 855–864 (1970)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. K. Sterling, M.A. Brenner, E.S. Newman, Conversion of thyroxine to triiodothyronine in normal human subjects. Science 169, 1099–1100 (1970)

    Article  CAS  PubMed  Google Scholar 

  31. J.H. Oppenheimer et al. Specific nuclear triidothyronine binding sites in rat liver and kidney. J. Clin. Endocrinol. Metab. 35, 330–333 (1972)

    Article  CAS  PubMed  Google Scholar 

  32. A.R. Schadlow et al. Specific triiodothyronine binding sites in the anterior pituitary of the rat. Science 176, 1252–1254 (1972)

    Article  CAS  PubMed  Google Scholar 

  33. H.H. Samuels, J.S. Tsai, Thyroid hormone action in cell culture: demonstration of nuclear receptors in intact cells and isolated nuclei. Proc. Natl Acad. Sci. USA 12, 3488–3494 (1973)

    Article  Google Scholar 

  34. J.H. Oppenheimer et al. Limited binding capacity sites for L-triiodothyronine in rat liver nuclei. Nuclear-cytoplasmic interrelation, binding constants, and cross- reactivity with L-thyroxine. J. Clin. Invest. 53, 768–677 (1974)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. M.I. Surks, J.H. Oppenheimer, Concentration of L-thyroxine and L-triiodothyronine specifically bound to nuclear receptors in rat liver and kidney. J. Clin. Invest. 60, 555–562 (1977)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. T.J. Visser et al. Subcellular localization of a rat liver enzyme converting thyroxine into tri- iodothyronine and possible involvement of essential thiol groups. Biochem. J. 157, 479–482 (1976)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. J.E. Silva, P.R. Larsen, Contributions of plasma triiodothyronine and local thyroxine monodeiodination to triiodothyronine and nuclear triiodothyronine receptor saturation in pituitary, liver, and kidney of hypothyroid rats. Further evidence relating saturation of pituitary nuclear triiodothyronine receptors and the acute inhibition of thyroid-stimulating hormone release. J. Clin. Invest. 61, 1247–1259 (1978)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. P.R. Larsen et al. Inhibition of intrapituitary thyroxine to 3.5.3’-triiodothyronine conversion prevents the acute suppression of thyrotropin release by thyroxine in hypothyroid rats. J. Clin. Invest. 64, 117–128 (1979)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. T.J. Visser et al. Evidence for two pathways of iodothyronine 5’-deiodination in rat pituitary that differ in kinetics, propylthiouracil sensitivity, and response to hypothyroidism. J. Clin. Invest. 71, 992–1002 (1983)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. T.J. Visser. et al. Kinetic evidence suggesting two mechanisms for iodothyronine 5’-deiodination in rat cerebral cortex. Proc. Natl Acad. Sci. USA 79, 5080–5084 (1982)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. A.C. Bianco et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endo. Rev. 23, 38–89 (2002)

    Article  CAS  Google Scholar 

  42. M.J. Berry, L. Banu, P.R. Larsen, Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature 349, 438–440 (1991)

    Article  CAS  PubMed  Google Scholar 

  43. J.C. Davey et al. Cloning of a cDNA for the type II iodothyronine deiodinase. J. Biol. Chem. 270, 26786–26789 (1995)

    Article  CAS  PubMed  Google Scholar 

  44. W. Croteau et al. Cloning of the mammalian type II iodothyronine deiodinase: a selenoprotein differentially expressed and regulated in the human brain and other tissues. J. Clin. Invest. 98, 405–417 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. M.J. Schneider et al. Targeted disruption of the type 2 selenodeiodinase gene (Dio2) results in a phenotype of pituitary resistance to T4. Mol. Endocrinol. 15, 2137–2148 (2001)

    Article  CAS  PubMed  Google Scholar 

  46. M.J. Schneider et al. Targeted disruption of the type1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 147, 580–589 (2006)

    Article  CAS  PubMed  Google Scholar 

  47. V.A. Galton et al. Life without T4 to T3 conversion: studies in mice devoid of the 5’-deiodinases. Endocrinology 150, 2957–2963 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. F.R. Crantz, J.E. Silva, P.R. Larsen, An analysis of the sources and quantity of 3,5,3’-triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum. Endocrinology 110, 367–375 (1982)

    Article  CAS  PubMed  Google Scholar 

  49. K. Sorimachi, J. Robbins, Metabolism of thyroid hormones by cultured monkey hepatocarcinoma cells. Nonphenolic ring dieodination and sulfation. J. Biol. Chem. 252, 4458–4463 (1977)

    CAS  PubMed  Google Scholar 

  50. V.A. Galton et al. Pregnant rat uterus expresses high levels of the type 3 iodothyronine deiodinase. J. Clin. Invest. 103, 979–987 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. S.A. Huang et al. Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium. J. Clin. Endo. Metab. 88, 1384–1388 (2003)

    Article  CAS  Google Scholar 

  52. L. Ng et al. A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 150, 1952–1960 (2009)

    Article  CAS  PubMed  Google Scholar 

  53. D.L. St. Germain et al. A thyroid hormone regulated gene in Xenopus laevis encodes a type III iodothyronine 5-deiodinase. Proc. Natl Acad. Sci. USA 91, 7767–7771 (1994).

    Article  Google Scholar 

  54. W. Croteau et al. Cloning and expression of a cDNA for a mammalian type III iodothyronine deiodinase. J. Biol. Chem. 270, 16569–16575 (1995)

    Article  CAS  PubMed  Google Scholar 

  55. A. Hernandez et al. Type 3 deiodinase deficiency results in functional abnormalities at multiple levels of the thyroid axis. Endocrinology 148, 5680–5687 (2007)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Donald St. Germain for the helpful suggestions he made after reading the paper.

Author information

Authors and Affiliations

  1. Divisions of Endocrinology and Medical Oncology, Mayo Clinic, Rochester, MN, USA

    John C. Morris

  2. Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Valerie Anne Galton

Authors
  1. John C. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valerie Anne Galton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valerie Anne Galton.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morris, J.C., Galton, V.A. The isolation of thyroxine (T4), the discovery of 3,5,3’-triiodothyronine (T3), and the identification of the deiodinases that generate T3 from T4: An historical review. Endocrine 66, 3–9 (2019). https://doi.org/10.1007/s12020-019-01990-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-01990-1

Search

Navigation