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. 1989 Nov;84(5):1650–1656. doi: 10.1172/JCI114343

Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.

J S LoPresti 1, A Eigen 1, E Kaptein 1, K P Anderson 1, C A Spencer 1, J T Nicoloff 1
PMCID: PMC304032  PMID: 2808705

Abstract

To elucidate the mechanisms involved in altering serum 3,3',5'-triiodothyronine (rT3) levels with absolute or relative low 3,5,3'-triiodothyronine (T3) states in man, agents capable of lowering circulating T3 levels were sequentially administered to six euthyroid subjects. These agents included propylthiouracil (PTU) (300 mg/6 h X 5 d), dexamethasone (DEX) (2 mg/6 h X 5 d), and thyroxine (T4) (3.0 mg load and 0.3 mg/d X 5 d). [125I] rT3 clearance rates and rT3 production rates were then determined. Increased serum rT3 levels and rT3/T4 values occurred with both PTU and DEX as compared with control, while T4 increased serum rT3 but did so without changing rT3/T4 values. The rT3 clearance rate was significantly decreased by PTU without altering production rate, while DEX increased the rT3 production rate without altering the rT3 clearance rate. T4 administration did not change rT3 clearance but proportionately increased rT3 production. These responses indicate that circulating rT3 predominantly originates from a non-PTU inhibitable deiodinase enzyme system located in extrahepatic tissues. This enzyme system appears to have a high capacity and low affinity for T4 and can be stimulated by DEX administration.

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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. Balsam A., Ingbar S. H. The influence of fasting, diabetes, and several pharmacological agents on the pathways of thyroxine metabolism in rat liver. J Clin Invest. 1978 Aug;62(2):415–424. doi: 10.1172/JCI109143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Balsam A., Sexton F., Borges M., Ingbar S. H. Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism. J Clin Invest. 1983 Oct;72(4):1234–1245. doi: 10.1172/JCI111079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bianchi R., Zucchelli G. C., Giannessi D., Pilo A., Mariani G., Carpi A., Toni M. G. Evaluation of triiodothyronine (T3) kinetics in normal subjects, in hypothyroid, and hyperthyroid patients using specific antiserum for the determination of labeled T3 in plasma. J Clin Endocrinol Metab. 1978 Feb;46(2):203–214. doi: 10.1210/jcem-46-2-203. [DOI] [PubMed] [Google Scholar]
  5. Braverman L. E., Vagenakis A., Downs P., Foster A. E., Sterling K., Ingbar S. H. Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man. J Clin Invest. 1973 May;52(5):1010–1017. doi: 10.1172/JCI107265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cavalieri R. R., Castle J. N., McMahon F. A. Effects of dexamethasone on kinetics and distribution of triiodothyronine in the rat. Endocrinology. 1984 Jan;114(1):215–221. doi: 10.1210/endo-114-1-215. [DOI] [PubMed] [Google Scholar]
  7. Chiraseveenuprapund P., Buergi U., Goswami A., Rosenberg I. N. Conversion of L-thyroxine to triiodothyronine in rat kidney homogenate. Endocrinology. 1978 Feb;102(2):612–622. doi: 10.1210/endo-102-2-612. [DOI] [PubMed] [Google Scholar]
  8. Chopra I. J. An assessment of daily production and significance of thyroidal secretion of 3, 3', 5'-triiodothyronine (reverse T3) in man. J Clin Invest. 1976 Jul;58(1):32–40. doi: 10.1172/JCI108456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chopra I. J., Chopra U., Smith S. R., Reza M., Solomon D. H. Reciprocal changes in serum concentrations of 3,3',5-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab. 1975 Dec;41(06):1043–1049. doi: 10.1210/jcem-41-6-1043. [DOI] [PubMed] [Google Scholar]
  10. Chopra I. J., Chua Teco G. N. Characteristics of inner ring (3 or 5) monodeiodination of 3,5-diiodothyronine in rat liver: evidence suggesting marked similarities of inner and outer ring deiodinases for iodothyronines. Endocrinology. 1982 Jan;110(1):89–97. doi: 10.1210/endo-110-1-89. [DOI] [PubMed] [Google Scholar]
  11. Chopra I. J., Williams D. E., Orgiazzi J., Solomon D. H. Opposite effects of dexamethasone on serum concentrations of 3,3',5'-triiodothyronine (reverse T3) and 3,3'5-triiodothyronine (T3). J Clin Endocrinol Metab. 1975 Nov;41(5):911–920. doi: 10.1210/jcem-41-5-911. [DOI] [PubMed] [Google Scholar]
  12. Corcoran J. M., Eastman C. J. Reverse triiodothyronine metabolism in euthyroid adults. Horm Metab Res. 1977 Nov;9(6):526–527. doi: 10.1055/s-0028-1095587. [DOI] [PubMed] [Google Scholar]
  13. Croxson M. S., Hall T. D., Nicoloff J. T. Combination drug therapy for treatment of hyperthyroid Grave's disease. J Clin Endocrinol Metab. 1977 Oct;45(4):623–630. doi: 10.1210/jcem-45-4-623. [DOI] [PubMed] [Google Scholar]
  14. DiStefano J. J., 3rd, Jang M., Malone T. K., Broutman M. Comprehensive kinetics of triiodothyronine production, distribution, and metabolism in blood and tissue pools of the rat using optimized blood-sampling protocols. Endocrinology. 1982 Jan;110(1):198–213. doi: 10.1210/endo-110-1-198. [DOI] [PubMed] [Google Scholar]
  15. Duick D. S., Warren D. W., Nicoloff J. T., Otis C. L., Croxson M. S. Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab. 1974 Dec;39(6):1151–1154. doi: 10.1210/jcem-39-6-1151. [DOI] [PubMed] [Google Scholar]
  16. Eisenstein Z., Hagg S., Vagenakis A. G., Fang S. L., Ransil B., Burger A., Balsam A., Braverman L. E., Ingbar S. H. Effect of starvation on the production and peripheral metabolism of 3,3',5'-triiodothyronine in euthyroid obese subjects. J Clin Endocrinol Metab. 1978 Oct;47(4):889–893. doi: 10.1210/jcem-47-4-889. [DOI] [PubMed] [Google Scholar]
  17. Engler D., Burger A. G. The deiodination of the iodothyronines and of their derivatives in man. Endocr Rev. 1984 Spring;5(2):151–184. doi: 10.1210/edrv-5-2-151. [DOI] [PubMed] [Google Scholar]
  18. Faber J., Busch-Sørensen M., Rogowski P., Kirkegaard C., Siersbaek-Nielsen K., Friis T. Urinary excretion of free and conjugated 3',5'-diiodothyronine and 3,3'-diiodothyronine. J Clin Endocrinol Metab. 1981 Sep;53(3):587–593. doi: 10.1210/jcem-53-3-587. [DOI] [PubMed] [Google Scholar]
  19. Faber J., Faber O. K., Lund B., Kirkegaard C., Wahren J. Hepatic extraction and renal production of 3,3'-diiodothyronine and 3',5'-diiodothyronine in man. J Clin Invest. 1980 Nov;66(5):941–945. doi: 10.1172/JCI109962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Faber J., Thomsen H. F., Lumholtz I. B., Kirkegaard C., Siersbaek-Nielsen K., Friis T. Kinetic studies of thyroxine, 3,5,3'-triiodothyronine, 3,3,5'-triiodothyronine, 3',5'-diiodothyronine, 3,3'-diiodothyronine, and 3'-monoiodothyronine in patients with liver cirrhosis. J Clin Endocrinol Metab. 1981 Nov;53(5):978–984. doi: 10.1210/jcem-53-5-978. [DOI] [PubMed] [Google Scholar]
  21. Fay M., Roti E., Fang S. L., Wright G., Braverman L. E., Emerson C. H. The effects of propylthiouracil, iodothyronines, and other agents on thyroid hormone metabolism in human placenta. J Clin Endocrinol Metab. 1984 Feb;58(2):280–286. doi: 10.1210/jcem-58-2-280. [DOI] [PubMed] [Google Scholar]
  22. Gavin L., Castle J., McMahon F., Martin P., Hammond M., Cavalieri R. R. Extrathyroidal conversion of thyroxine to 3,3',5'-triiodothyronine (reverse-T3) and to 3,5,3'-triiodothyronine (T3) in humans. J Clin Endocrinol Metab. 1977 Apr;44(4):733–742. doi: 10.1210/jcem-44-4-733. [DOI] [PubMed] [Google Scholar]
  23. Geffner D. L., Azukizawa M., Hershman J. M. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. J Clin Invest. 1975 Feb;55(2):224–229. doi: 10.1172/JCI107925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Huang T. S., Chopra I. J., Beredo A., Solomon D. H., Chua TecoGN Skin is an active site for the inner ring monodeiodination of thyroxine to 3,3',5'-triiodothyronine. Endocrinology. 1985 Nov;117(5):2106–2113. doi: 10.1210/endo-117-5-2106. [DOI] [PubMed] [Google Scholar]
  25. Jennings A. S., Ferguson D. C. Effect of dexamethasone on triiodothyronine production in the perfused rat liver and kidney. Endocrinology. 1984 Jan;114(1):31–36. doi: 10.1210/endo-114-1-31. [DOI] [PubMed] [Google Scholar]
  26. Kaplan M. M., Schimmel M., Utiger R. D. Changes in serum 3,3',5'-triiodothyronine (reverse T3) concentrations with altered thyroid hormone secretion and metabolism. J Clin Endocrinol Metab. 1977 Sep;45(3):447–456. doi: 10.1210/jcem-45-3-447. [DOI] [PubMed] [Google Scholar]
  27. Kaplan M. M. The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function. Neuroendocrinology. 1984 Mar;38(3):254–260. doi: 10.1159/000123900. [DOI] [PubMed] [Google Scholar]
  28. Kaplan M. M., Yaskoski K. A. Phenolic and tyrosyl ring deiodination of iodothyronines in rat brain homogenates. J Clin Invest. 1980 Sep;66(3):551–562. doi: 10.1172/JCI109887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kaptein E. M., Egodage P. M., Hoopes M. T., Burger A. G. Amiodarone alters thyroxine transfer and distribution in humans. Metabolism. 1988 Dec;37(12):1107–1113. doi: 10.1016/0026-0495(88)90185-0. [DOI] [PubMed] [Google Scholar]
  30. Kaptein E. M., Robinson W. J., Grieb D. A., Nicoloff J. T. Peripheral serum thyroxine, triiodothyronine and reverse triiodothyronine kinetics in the low thyroxine state of acute nonthyroidal illnesses. A noncompartmental analysis. J Clin Invest. 1982 Mar;69(3):526–535. doi: 10.1172/JCI110478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lum S. M., Nicoloff J. T., Spencer C. A., Kaptein E. M. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest. 1984 Feb;73(2):570–575. doi: 10.1172/JCI111245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. McCann U. D., Shaw E. A., Kaplan M. M. Iodothyronine deiodination reaction types in several rat tissues: effects of age, thyroid status, and glucocorticoid treatment. Endocrinology. 1984 May;114(5):1513–1521. doi: 10.1210/endo-114-5-1513. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Nicoloff J. T. A new method for the measurement of acute alterations in thyroxine deiodination rate in man. J Clin Invest. 1970 Feb;49(2):267–273. doi: 10.1172/JCI106236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Osathanondh R., Chopra I. J., Tulchinsky D. Effects of dexamethasone on fetal and maternal thyroxine, triiodothyronine, reverse triiodothyronine, and thyrotropin levels. J Clin Endocrinol Metab. 1978 Dec;47(6):1236–1239. doi: 10.1210/jcem-47-6-1236. [DOI] [PubMed] [Google Scholar]
  36. Pittman C. S., Shimizu T., Burger A., Chambers J. B., Jr The nondeiodinative pathways of thyroxine metabolism: 3,5,3',5-tetraiodothyroacetic acid turnover in normal and fasting human subjects. J Clin Endocrinol Metab. 1980 Apr;50(4):712–716. doi: 10.1210/jcem-50-4-712. [DOI] [PubMed] [Google Scholar]
  37. Rogowski P., Faber J., Siersbaek-Nielsen K. Renal handling of 3,3',5'-triiodothyronine (reverse T3) compared to thyroxine and 3,5,3'-triiodothyronine in different thyroid function states in man. Acta Endocrinol (Copenh) 1980 Jul;94(3):337–340. doi: 10.1530/acta.0.0940337. [DOI] [PubMed] [Google Scholar]
  38. Roti E., Fang S. L., Braverman L. E., Emerson C. H. Rat placenta is an active site of inner ring deiodination of thyroxine and 3,3',5-triiodothyronine. Endocrinology. 1982 Jan;110(1):34–37. doi: 10.1210/endo-110-1-34. [DOI] [PubMed] [Google Scholar]
  39. Saberi M., Sterling F. H., Utiger R. D. Reduction in extrathyroidal triiodothyronine production by propylthiouracil in man. J Clin Invest. 1975 Feb;55(2):218–223. doi: 10.1172/JCI107924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Silva J. E., Gordon M. B., Crantz F. R., Leonard J. L., Larsen P. R. Qualitative and quantitative differences in the pathways of extrathyroidal triiodothyronine generation between euthyroid and hypothyroid rats. J Clin Invest. 1984 Apr;73(4):898–907. doi: 10.1172/JCI111313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Silva J. E., Matthews P. Thyroid hormone metabolism and the source of plasma triiodothyronine in 2-week-old rats: effects of thyroid status. Endocrinology. 1984 Jun;114(6):2394–2405. doi: 10.1210/endo-114-6-2394. [DOI] [PubMed] [Google Scholar]
  42. Smallridge R. C., Wartofsky L., Desjardins R. E., Burman K. D. Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects. J Clin Endocrinol Metab. 1978 Aug;47(2):345–349. doi: 10.1210/jcem-47-2-345. [DOI] [PubMed] [Google Scholar]
  43. Spencer C. A., Lum S. M., Wilber J. F., Kaptein E. M., Nicoloff J. T. Dynamics of serum thyrotropin and thyroid hormone changes in fasting. J Clin Endocrinol Metab. 1983 May;56(5):883–888. doi: 10.1210/jcem-56-5-883. [DOI] [PubMed] [Google Scholar]
  44. Suda A. K., Pittman C. S., Shimizu T., Chambers J. B., Jr The production and metabolism of 3,5,3'-triiodothyronine and 3,3',5-triiodothyronine in normal and fasting subjects. J Clin Endocrinol Metab. 1978 Dec;47(6):1311–1319. doi: 10.1210/jcem-47-6-1311. [DOI] [PubMed] [Google Scholar]
  45. Visser T. J., Docter R., Hennemann G. Radioimmunoassay of reverse tri-iodothyronine. J Endocrinol. 1977 May;73(2):395–396. doi: 10.1677/joe.0.0730395. [DOI] [PubMed] [Google Scholar]
  46. 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]

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