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. 1987 Jun;79(6):1740–1748. doi: 10.1172/JCI113014

Metabolism of reverse triiodothyronine by isolated rat hepatocytes.

S J Rooda, M A van Loon, T J Visser
PMCID: PMC424516  PMID: 3584467

Abstract

Reverse triiodothyronine (rT3) is metabolized predominantly by outer ring deiodination to 3,3'-diiodothyronine (3,3'-T2) in the liver. Metabolism of rT3 and 3,3'-T2 by isolated rat hepatocytes was analyzed by Sephadex LH-20 chromatography, high performance liquid chromatography, and radioimmunoassay, with closely agreeing results. Deiodinase activity was inhibited with propylthiouracil (PTU) and sulfotransferase activity by sulfate depletion or addition of salicylamide or dichloronitrophenol. Normally, little 3,3'-T2 production from rT3 was observed, and 125I- was the main product of both 3,[3'-125I]T2 and [3',5'-125I]rT3. PTU inhibited rT3 metabolism but did not affect 3,3'-T2 clearance as explained by accumulation of 3,3'-T2 sulfate. Inhibition of sulfation did not affect rT3 clearance but 3,3'-T2 metabolism was greatly diminished. The decrease in I- formation from rT3 was compensated by an increased recovery of 3,3'-T2 up to 70% of rT3 metabolized. In conclusion, significant production of 3,3'-T2 from rT3 by rat hepatocytes is only observed if further sulfation is inhibited.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Dills R. L., Klaassen C. D. The effect of inhibitors of mitochondrial energy production on hepatic glutathione, UDP-glucuronic acid, and adenosine 3'-phosphate-5'-phosphosulfate concentrations. Drug Metab Dispos. 1986 Mar-Apr;14(2):190–196. [PubMed] [Google Scholar]
  2. 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]
  3. Engler D., Merkelbach U., Steiger G., Burger A. G. The monodeiodination of triiodothyronine and reverse triiodothyronine in man: a quantitative evaluation of the pathway by the use of turnover rate techniques. J Clin Endocrinol Metab. 1984 Jan;58(1):49–61. doi: 10.1210/jcem-58-1-49. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Flock E. V., Owen C. A., Jr Metabolism of thyroid hormones and some derivatives in isolated, perfused rat liver. Am J Physiol. 1965 Nov;209(5):1039–1045. doi: 10.1152/ajplegacy.1965.209.5.1039. [DOI] [PubMed] [Google Scholar]
  6. Hidal J. T., Kaplan M. M. Characteristics of thyroxine 5'-deiodination in cultured human placental cells. Regulation by iodothyronines. J Clin Invest. 1985 Sep;76(3):947–955. doi: 10.1172/JCI112094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Howell S. R., Hazelton G. A., Klaassen C. D. Depletion of hepatic UDP-glucuronic acid by drugs that are glucuronidated. J Pharmacol Exp Ther. 1986 Mar;236(3):610–614. [PubMed] [Google Scholar]
  8. 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]
  9. Koike M., Sugeno K., Hirata M. Sulfoconjugation and glucuronidation of salicylamide in isolated rat hepatocytes. J Pharm Sci. 1981 Mar;70(3):308–311. doi: 10.1002/jps.2600700322. [DOI] [PubMed] [Google Scholar]
  10. Koster H., Halsema I., Scholtens E., Meerman J. H., Pang K. S., Mulder G. J. Selective inhibition of sulfate conjugation in the rat: pharmacokinetics and characterization of the inhibitory effect of 2,6-dichloro-4-nitrophenol. Biochem Pharmacol. 1982 May 15;31(10):1919–1924. doi: 10.1016/0006-2952(82)90498-1. [DOI] [PubMed] [Google Scholar]
  11. Koster H., Halsema I., Scholtens E., Pang K. S., Mulder G. J. Kinetics of sulfation and glucuronidation of harmol in the perfused rat liver preparation. Disappearance of aberrances in glucuronidation kinetics by inhibition of sulfation. Biochem Pharmacol. 1982 Oct 1;31(19):3023–3028. doi: 10.1016/0006-2952(82)90074-0. [DOI] [PubMed] [Google Scholar]
  12. Krenning E., Docter R., Bernard B., Visser T., Hennemann G. Characteristics of active transport of thyroid hormone into rat hepatocytes. Biochim Biophys Acta. 1981 Sep 4;676(3):314–320. doi: 10.1016/0304-4165(81)90165-3. [DOI] [PubMed] [Google Scholar]
  13. Levy G., Yamada H. Drug biotransformation interactions in man. 3. Acetaminophen and salicylamide. J Pharm Sci. 1971 Feb;60(2):215–221. doi: 10.1002/jps.2600600212. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Mol J. A., Visser T. J. Synthesis and some properties of sulfate esters and sulfamates of iodothyronines. Endocrinology. 1985 Jul;117(1):1–7. doi: 10.1210/endo-117-1-1. [DOI] [PubMed] [Google Scholar]
  17. Moldéus P., Andersson B., Gergely V. Regulation of glucuronidation and sulfate conjugation in isolated hepatocytes. Drug Metab Dispos. 1979 Nov-Dec;7(6):416–419. [PubMed] [Google Scholar]
  18. Otten M. H., Hennemann G., Docter R., Visser T. J. Metabolism of 3,3'-diiodothyronine in rat hepatocytes: interaction of sulfation with deiodination. Endocrinology. 1984 Sep;115(3):887–894. doi: 10.1210/endo-115-3-887. [DOI] [PubMed] [Google Scholar]
  19. Otten M. H., Mol J. A., Visser T. J. Sulfation preceding deiodination of iodothyronines in rat hepatocytes. Science. 1983 Jul 1;221(4605):81–83. doi: 10.1126/science.6857270. [DOI] [PubMed] [Google Scholar]
  20. ROCHE J., MICHEL R., NUNEZ J., JACQUEMIN C. On the metabolism of 3,3'-diiodothyronine and 3,3',5'-triiodothyronine. Endocrinology. 1959 Sep;65:402–407. doi: 10.1210/endo-65-3-402. [DOI] [PubMed] [Google Scholar]
  21. ROCHE J., MICHEL R., NUNEZ J., WOLF W. Sur la presence dans le plasma de la 3:3'-diiodothyronine, nouvelle hormone thyroïdienne. C R Seances Soc Biol Fil. 1955 May;149(9-10):884–887. [PubMed] [Google Scholar]
  22. ROCHE J., MICHEL R., NUNEZ U., WOLF W. Sur deux constituants hormonaux nouveaux du corps thyroïde: la 3:3'-diiodothyronine et la 3:3':5'-triiodothyronine. Biochim Biophys Acta. 1955 Sep;18(1):149–150. doi: 10.1016/0006-3002(55)90027-5. [DOI] [PubMed] [Google Scholar]
  23. Sekura R. D., Sato K., Cahnmann H. J., Robbins J., Jakoby W. B. Sulfate transfer to thyroid hormones and their analogs by hepatic aryl sulfotransferases. Endocrinology. 1981 Feb;108(2):454–456. doi: 10.1210/endo-108-2-454. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. 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]
  27. Visser T. J., Fekkes D., Docter R., Hennemann G. Kinetics of enzymic reductive deiodination of iodothyronines. Effect of pH. Biochem J. 1979 Jun 1;179(3):489–495. doi: 10.1042/bj1790489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Visser T. J., Krieger-Quist L. M., Docter R., Hennemann G. Radioimmunoassay of 3,3'-di-iodothyronine in unextracted serum: the effect of endogenous tri-iodothyronine. J Endocrinol. 1978 Dec;79(3):357–362. doi: 10.1677/joe.0.0790357. [DOI] [PubMed] [Google Scholar]
  29. Visser T. J., Mol J. A., Otten M. H. Rapid deiodination of triiodothyronine sulfate by rat liver microsomal fraction. Endocrinology. 1983 Apr;112(4):1547–1549. doi: 10.1210/endo-112-4-1547. [DOI] [PubMed] [Google Scholar]
  30. Visser T. J., Otten M. H., Mol J. A., Docter R., Hennemann G. Sulfation facilitates hepatic deiodination of iodothyronines. Horm Metab Res Suppl. 1984;14:35–41. [PubMed] [Google Scholar]
  31. WYNN J., FORE W. THE EFFECT OF HINDERED PHENOLS ON MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION. J Biol Chem. 1965 Apr;240:1766–1771. [PubMed] [Google Scholar]
  32. Wartofsky L., Burman K. D. Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome". Endocr Rev. 1982 Spring;3(2):164–217. doi: 10.1210/edrv-3-2-164. [DOI] [PubMed] [Google Scholar]
  33. Waschek J. A., Fielding R. M., Pond S. M., Rubin G. M., Effeney D. J., Tozer T. N. Dose-dependent sulfoconjugation of salicylamide in dogs: effect of sulfate depletion or administration. J Pharmacol Exp Ther. 1985 Aug;234(2):431–434. [PubMed] [Google Scholar]
  34. Zucchelli G. C., Pilo A., Giannessi D., Bianchi R., Cazzuola F., Molea N. Labeled metabolites appearing in human serum after 125I-triiodothyronine (T3) administration: a quantitative reappraisal. Metabolism. 1980 Oct;29(11):1031–1036. doi: 10.1016/0026-0495(80)90212-7. [DOI] [PubMed] [Google Scholar]

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