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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Aug 15;98(4):962–968. doi: 10.1172/JCI118880

Type 2 iodothyronine deiodinase is highly expressed in human thyroid.

D Salvatore 1, H Tu 1, J W Harney 1, P R Larsen 1
PMCID: PMC507511  PMID: 8770868

Abstract

Type 2 iodothyronine deiodinase (D2) is a recently cloned selenodeiodinase thought to provide intracellular 3,5,3' triiodothyronine (T3) to a restricted group of tissues. We report here the presence of D2 mRNA in human thyroid at levels 50-150-fold higher than in placenta. Surprisingly, while type 1 deiodinase (D1) is known to be present in human thyroid, D2 has not been evaluated previously. D2 mRNA was especially high in thyroids from Graves' patients and in follicular adenomas. Stimulated thyroids had higher D2 to D1 mRNA ratios than normal or multinodular glands suggesting differential regulation of D1 and D2 expression. Microsomes from normal, Graves', and TSH-stimulated thyroids contained low Km D2 activity resistant to propylthiouracil (1 mM) or to inactivation by N-bromoacetyl T3, agents which block or inactivate D1. At 2 nM thyroxine (T4), 100 times the physiological-free T4 levels, 60-80% of T4 to T3 conversion in stimulated, but only 27% of that in normal thyroids, is catalyzed by D2. We conclude that intrathyroidal T4 to T3 conversion by D2 may contribute significantly to the relative increase in thyroidal T3 production in patients with Graves' disease, toxic adenomas, and, perhaps, iodine deficiency.

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Selected References

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  1. Abuid J., Larsen P. R. Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Clin Invest. 1974 Jul;54(1):201–208. doi: 10.1172/JCI107744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barge R. M., Mills I., Silva J. E., Larsen P. R. Phorbol esters, protein kinase C, and thyroxine 5'-deiodinase in brown adipocytes. Am J Physiol. 1988 Mar;254(3 Pt 1):E323–E327. doi: 10.1152/ajpendo.1988.254.3.E323. [DOI] [PubMed] [Google Scholar]
  3. Berry M. J., Banu L., Harney J. W., Larsen P. R. Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons. EMBO J. 1993 Aug;12(8):3315–3322. doi: 10.1002/j.1460-2075.1993.tb06001.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berry M. J., Banu L., Larsen P. R. Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature. 1991 Jan 31;349(6308):438–440. doi: 10.1038/349438a0. [DOI] [PubMed] [Google Scholar]
  5. Berry M. J., Kates A. L., Larsen P. R. Thyroid hormone regulates type I deiodinase messenger RNA in rat liver. Mol Endocrinol. 1990 May;4(5):743–748. doi: 10.1210/mend-4-5-743. [DOI] [PubMed] [Google Scholar]
  6. Berry M. J., Kieffer J. D., Harney J. W., Larsen P. R. Selenocysteine confers the biochemical properties characteristic of the type I iodothyronine deiodinase. J Biol Chem. 1991 Aug 5;266(22):14155–14158. [PubMed] [Google Scholar]
  7. Berry M. J., Maia A. L., Kieffer J. D., Harney J. W., Larsen P. R. Substitution of cysteine for selenocysteine in type I iodothyronine deiodinase reduces the catalytic efficiency of the protein but enhances its translation. Endocrinology. 1992 Oct;131(4):1848–1852. doi: 10.1210/endo.131.4.1396330. [DOI] [PubMed] [Google Scholar]
  8. Borges M., Ingbar S. H., Silva J. E. Iodothyronine deiodinase activities in FRTL5 cells: predominance of type I 5'-deiodinase. Endocrinology. 1990 Jun;126(6):3059–3068. doi: 10.1210/endo-126-6-3059. [DOI] [PubMed] [Google Scholar]
  9. Brent G. A., Larsen P. R., Harney J. W., Koenig R. J., Moore D. D. Functional characterization of the rat growth hormone promoter elements required for induction by thyroid hormone with and without a co-transfected beta type thyroid hormone receptor. J Biol Chem. 1989 Jan 5;264(1):178–182. [PubMed] [Google Scholar]
  10. Cheron R. G., Kaplan M. M., Larsen P. R. Physiological and pharmacological influences on thyroxine to 3,5,3'-triiodothyronine conversion and nuclear 3,5,3'-triiodothyronine binding in rat anterior pituitary. J Clin Invest. 1979 Nov;64(5):1402–1414. doi: 10.1172/JCI109598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Davey J. C., Becker K. B., Schneider M. J., St Germain D. L., Galton V. A. Cloning of a cDNA for the type II iodothyronine deiodinase. J Biol Chem. 1995 Nov 10;270(45):26786–26789. doi: 10.1074/jbc.270.45.26786. [DOI] [PubMed] [Google Scholar]
  12. Dumont J. E., Lamy F., Roger P., Maenhaut C. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiol Rev. 1992 Jul;72(3):667–697. doi: 10.1152/physrev.1992.72.3.667. [DOI] [PubMed] [Google Scholar]
  13. Goswami A., Rosenberg I. N. Iodothyronine 5'-deiodinase in rat kidney microsomes. Kinetic behavior at low substrate concentrations. J Clin Invest. 1984 Dec;74(6):2097–2106. doi: 10.1172/JCI111634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Itagaki Y., Yoshida K., Ikeda H., Kaise K., Kaise N., Yamamoto M., Sakurada T., Yoshinaga K. Thyroxine 5'-deiodinase in human anterior pituitary tumors. J Clin Endocrinol Metab. 1990 Aug;71(2):340–344. doi: 10.1210/jcem-71-2-340. [DOI] [PubMed] [Google Scholar]
  15. Izumi M., Larsen P. R. Triiodothyronine, thyroxine, and iodine in purified thyroglobulin from patients with Graves' disease. J Clin Invest. 1977 Jun;59(6):1105–1112. doi: 10.1172/JCI108734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kaplan M. M., Pan C. Y., Gordon P. R., Lee J. K., Gilchrest B. A. Human epidermal keratinocytes in culture convert thyroxine to 3,5,3'-triiodothyronine by type II iodothyronine deiodination: a novel endocrine function of the skin. J Clin Endocrinol Metab. 1988 Apr;66(4):815–822. doi: 10.1210/jcem-66-4-815. [DOI] [PubMed] [Google Scholar]
  17. Larsen P. R., Berry M. J. Nutritional and hormonal regulation of thyroid hormone deiodinases. Annu Rev Nutr. 1995;15:323–352. doi: 10.1146/annurev.nu.15.070195.001543. [DOI] [PubMed] [Google Scholar]
  18. Larsen P. R., Silva J. E., Kaplan M. M. Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications. Endocr Rev. 1981 Winter;2(1):87–102. doi: 10.1210/edrv-2-1-87. [DOI] [PubMed] [Google Scholar]
  19. Laurberg P., Boye N. Propylthiouracil, ipodate, dexamethasone and periods of fasting induce different variations in serum rT3 in dogs. Metabolism. 1984 Apr;33(4):323–325. doi: 10.1016/0026-0495(84)90191-4. [DOI] [PubMed] [Google Scholar]
  20. Laurberg P. Mechanisms governing the relative proportions of thyroxine and 3,5,3'-triiodothyronine in thyroid secretion. Metabolism. 1984 Apr;33(4):379–392. doi: 10.1016/0026-0495(84)90203-8. [DOI] [PubMed] [Google Scholar]
  21. Leonard J. L., Silva J. E., Kaplan M. M., Mellen S. A., Visser T. J., Larsen P. R. Acute posttranscriptional regulation of cerebrocortical and pituitary iodothyronine 5'-deiodinases by thyroid hormone. Endocrinology. 1984 Mar;114(3):998–1004. doi: 10.1210/endo-114-3-998. [DOI] [PubMed] [Google Scholar]
  22. LoPresti J. S., Eigen A., Kaptein E., Anderson K. P., Spencer C. A., Nicoloff J. T. Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man. J Clin Invest. 1989 Nov;84(5):1650–1656. doi: 10.1172/JCI114343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mandel S. J., Berry M. J., Kieffer J. D., Harney J. W., Warne R. L., Larsen P. R. Cloning and in vitro expression of the human selenoprotein, type I iodothyronine deiodinase. J Clin Endocrinol Metab. 1992 Oct;75(4):1133–1139. doi: 10.1210/jcem.75.4.1400883. [DOI] [PubMed] [Google Scholar]
  24. Mills I., Raasmaja A., Moolten N., Lemack G., Silva J. E., Larsen P. R. Effect of thyroid status on catecholamine stimulation of thyroxine 5'-deiodinase in brown adipocytes. Am J Physiol. 1989 Jan;256(1 Pt 1):E74–E79. doi: 10.1152/ajpendo.1989.256.1.E74. [DOI] [PubMed] [Google Scholar]
  25. Mol J. A., Docter R., Hennemann G., Visser T. J. Modification of rat liver iodothyronine 5'-deiodinase activity with diethylpyrocarbonate and rose bengal; evidence for an active site histidine residue. Biochem Biophys Res Commun. 1984 Apr 16;120(1):28–36. doi: 10.1016/0006-291x(84)91409-8. [DOI] [PubMed] [Google Scholar]
  26. Mol J. A., Visser T. J. Rapid and selective inner ring deiodination of thyroxine sulfate by rat liver deiodinase. Endocrinology. 1985 Jul;117(1):8–12. doi: 10.1210/endo-117-1-8. [DOI] [PubMed] [Google Scholar]
  27. Raasmaja A., Larsen P. R. Alpha 1- and beta-adrenergic agents cause synergistic stimulation of the iodothyronine deiodinase in rat brown adipocytes. Endocrinology. 1989 Nov;125(5):2502–2509. doi: 10.1210/endo-125-5-2502. [DOI] [PubMed] [Google Scholar]
  28. Salvatore D., Bartha T., Harney J. W., Larsen P. R. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology. 1996 Aug;137(8):3308–3315. doi: 10.1210/endo.137.8.8754756. [DOI] [PubMed] [Google Scholar]
  29. Salvatore D., Low S. C., Berry M., Maia A. L., Harney J. W., Croteau W., St Germain D. L., Larsen P. R. Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. J Clin Invest. 1995 Nov;96(5):2421–2430. doi: 10.1172/JCI118299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Silva J. E., Larsen P. R. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature. 1983 Oct 20;305(5936):712–713. doi: 10.1038/305712a0. [DOI] [PubMed] [Google Scholar]
  31. Silva J. E., Larsen P. R. Pituitary nuclear 3,5,3'-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science. 1977 Nov 11;198(4317):617–620. doi: 10.1126/science.199941. [DOI] [PubMed] [Google Scholar]
  32. Silva J. E., Larsen P. R. Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats. J Clin Invest. 1985 Dec;76(6):2296–2305. doi: 10.1172/JCI112239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Silva J. E., Mellen S., Larsen P. R. Comparison of kidney and brown adipose tissue iodothyronine 5'-deiodinases. Endocrinology. 1987 Aug;121(2):650–656. doi: 10.1210/endo-121-2-650. [DOI] [PubMed] [Google Scholar]
  34. Toyoda N., Harney J. W., Berry M. J., Larsen P. R. Identification of critical amino acids for 3,5,3'-triiodothyronine deiodination by human type 1 deiodinase based on comparative functional-structural analyses of the human, dog, and rat enzymes. J Biol Chem. 1994 Aug 12;269(32):20329–20334. [PubMed] [Google Scholar]
  35. Toyoda N., Nishikawa M., Mori Y., Yoshimura M., Masaki H., Gondou A., Yonemoto T., Inada M. Identification of a 27-kilodalton protein with the properties of type I iodothyronine 5'-deiodinase in human thyroid gland. J Clin Endocrinol Metab. 1992 Mar;74(3):533–538. doi: 10.1210/jcem.74.3.1740487. [DOI] [PubMed] [Google Scholar]
  36. Visser T. J., Kaplan M. M., Leonard J. L., Larsen P. R. Evidence for two pathways of iodothyronine 5'-deiodination in rat pituitary that differ in kinetics, propylthiouracil sensitivity, and response to hypothyroidism. J Clin Invest. 1983 Apr;71(4):992–1002. doi: 10.1172/JCI110854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Visser T. J., Kaptein E., Terpstra O. T., Krenning E. P. Deiodination of thyroid hormone by human liver. J Clin Endocrinol Metab. 1988 Jul;67(1):17–24. doi: 10.1210/jcem-67-1-17. [DOI] [PubMed] [Google Scholar]
  38. Visser T. J., Leonard J. L., Kaplan M. M., Larsen P. R. Kinetic evidence suggesting two mechanisms for iodothyronine 5'-deiodination in rat cerebral cortex. Proc Natl Acad Sci U S A. 1982 Aug;79(16):5080–5084. doi: 10.1073/pnas.79.16.5080. [DOI] [PMC free article] [PubMed] [Google Scholar]

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