Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 Oct;72(4):1234–1245. doi: 10.1172/JCI111079

Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

A Balsam, F Sexton, M Borges, S H Ingbar
PMCID: PMC370407  PMID: 6630509

Abstract

Studies were performed to elucidate the nature of the pathway of hepatic thyroxine (T4) metabolism that is activated by inhibitors of liver catalase. For this purpose, the metabolism of T4 in homogenates of rat liver was monitored with T4 labeled with 125I either at the 5'-position of the outer-ring (125I-beta-T4) or uniformly in both the outer and inner rings (125I-U-T4). In homogenates incubated with 125I-beta-T4 in an atmosphere of O2, the catalase inhibitor aminotriazole greatly enhanced T4 degradation, promoting the formation of large proportions of 125I-labeled iodide (125I-I-) and chromatographically immobile origin material (125I-OM), but only a minute proportion of 125I-labeled 3,5,3'-triiodothyronine (125I-T3) (T3 neogenesis). In an atmosphere of N2, in contrast, homogenates produced much larger proportions of 125I-T3, and aminotriazole had no effect. In incubations with 125I-U-T4, under aerobic conditions, control homogenates degraded T4 slowly; formation of 125I-labeled 3,5-diiodotyrosine (125I-DIT) was seen only occasionally and in minute proportions. However, in homogenates incubated under O2, but not N2, aminotriazole consistently elicited the formation of large proportions of 125I-DIT, indicating that the ether link of T4 was being cleaved by an O2-dependent process. Formation of 125I-DIT in the presence of aminotriazole and O2 was markedly inhibited by the substrates of peroxidase, aminoantipyrine, and guaiacol. GSH greatly attenuated the increase in DIT formation induced by aminotriazole, whereas the sulfhydryl inhibitor N-ethylmaleimide (NEM) activated the DIT-generating pathway, even in the absence of aminotriazole. Activation of the in vitro formation of 125I-DIT from 125I-U-T4 was also produced by the in vivo administration of aminotriazole or bacterial endotoxin, an agent that reduces hepatic catalase activity. Studies with 125I-DIT as substrate revealed it to be rapidly deiodinated by liver homogenates under aerobic conditions. Recovery of 125I-DIT from 125I-U-T4 was increased by the addition of the inhibitor of iodotyrosine dehalogenase, 3,5-dinitrotyrosine. However, as judged from studies conducted in parallel with radioiodine-labeled DIT and 125I-U-T4 as substrates, none of the factors that altered the proportion of 125I-DIT found after incubations with 125I-U-T4 did so by altering the degradation of the 125I-DIT formed. The factors that influenced DIT formation from T4 in rat liver had opposite effects on T3 neogenesis. Thus, aminotriazole, endotoxin, NEM, and an aerobic atmosphere, all of which enhanced DIT formation, were inhibitory to T3 neogenesis. In contrast, anaerobiosis and GSH inhibited ether-link cleavage of T4, but facilitated T3 neogenesis. The foregoing results suggest that a pathway for the ether-link cleavage of T4 to yield DIT is present in rat liver. Activity of this pathway, which appears to be peroxidase mediated, is inversely related to activity of the pathway for the T3 neogenesis. It is further suggested that this reciprocity reflects a reciprocal relationship between hepatic GSH and H2O2, the former increasing T3 formation and inhibiting DIT formation, and the latter producing opposite effects.

Full text

PDF
1234

Selected References

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

  1. Balsam A., Ingbar S. H. Observations on the factors that control the generation of triiodothyronine from thyroxine in rat liver and the nature of the defect induced by fasting. J Clin Invest. 1979 Jun;63(6):1145–1156. doi: 10.1172/JCI109408. [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. Bellabarba D., Peterson R. E., Sterling K. An improved method for chromatography of iodothyronines. J Clin Endocrinol Metab. 1968 Feb;28(2):305–307. doi: 10.1210/jcem-28-2-305. [DOI] [PubMed] [Google Scholar]
  4. Burger A. G., Engler D., Buergi U., Weissel M., Steiger G., Ingbar S. H., Rosin R. E., Babior B. M. Ether link cleavage is the major pathway of iodothyronine metabolism in the phagocytosing human leukocyte and also occurs in vivo in the rat. J Clin Invest. 1983 Apr;71(4):935–949. doi: 10.1172/JCI110848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cavalieri R. R. Impaired peripheral conversion of thyroxine to triiodothyronine,. Annu Rev Med. 1977;28:57–65. doi: 10.1146/annurev.me.28.020177.000421. [DOI] [PubMed] [Google Scholar]
  6. Chopra I. J., Solomon D. H., Chopra U., Young R. T., Chua Teco G. N. Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyronine. J Clin Endocrinol Metab. 1974 Sep;39(3):501–511. doi: 10.1210/jcem-39-3-501. [DOI] [PubMed] [Google Scholar]
  7. Chopra I. J. Sulfhydryl groups and the monodeiodination of thyroxine to triiodothyronine. Science. 1978 Feb 24;199(4331):904–906. doi: 10.1126/science.622575. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. GALTON V. A., INGBAR S. H. EFFECT OF CATALASE INHIBITORS ON THE DEIODINATION OF THYROXINE. Endocrinology. 1964 Apr;74:627–634. doi: 10.1210/endo-74-4-627. [DOI] [PubMed] [Google Scholar]
  10. GALTON V. A., INGBAR S. H. ROLE OF PEROXIDASE AND CATALASE IN THE PHYSIOLOGICAL DEIODINATION OF THYROXINE. Endocrinology. 1963 Nov;73:596–605. doi: 10.1210/endo-73-5-596. [DOI] [PubMed] [Google Scholar]
  11. Green W. L. Inhibition of thyroidal iodotyrosine deiodination by tyrosine analogues. Endocrinology. 1968 Aug;83(2):336–347. doi: 10.1210/endo-83-2-336. [DOI] [PubMed] [Google Scholar]
  12. Gregerman R. I., Solomon N. Acceleration of thyroxine and triiodothyronine turnover during bacterial pulmonary infections and fever: implications for the functional state of the thyroid during stress and in senescence. J Clin Endocrinol Metab. 1967 Jan;27(1):93–105. doi: 10.1210/jcem-27-1-93. [DOI] [PubMed] [Google Scholar]
  13. Inoue K., Taurog A. Digestion of 131I-labeled thyroid tissue with maximum recovery of 131I-iodothyronines. Endocrinology. 1967 Aug;81(2):319–332. doi: 10.1210/endo-81-2-319. [DOI] [PubMed] [Google Scholar]
  14. Kaplan M. M. Subcellular alterations causing reduced hepatic thyroxine-5'-monodeiodinase activity in fasted fats. Endocrinology. 1979 Jan;104(1):58–64. doi: 10.1210/endo-104-1-58. [DOI] [PubMed] [Google Scholar]
  15. Meinhold H., Beckert A., Wenzel K. W. Circulating diiodotyrosine: studies of its serum concentration, source, and turnover using radioimmunoassay after immunoextraction. J Clin Endocrinol Metab. 1981 Dec;53(6):1171–1178. doi: 10.1210/jcem-53-6-1171. [DOI] [PubMed] [Google Scholar]
  16. Nomura S., Pittman C. S., Chambers J. B., Jr, Buck M. W., Shimizu T. Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest. 1975 Sep;56(3):643–652. doi: 10.1172/JCI108134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. PLASKETT L. G. Studies on the degradation of thyroid hormones in vitro with compounds labelled in either ring. Biochem J. 1961 Mar;78:652–657. doi: 10.1042/bj0780652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pittman C. S., Chambers J. B., Jr The carbon structure of thyroxine metabolites in urine. Endocrinology. 1969 Apr;84(4):705–710. doi: 10.1210/endo-84-4-705. [DOI] [PubMed] [Google Scholar]
  19. Pittman C. S., Maruyama T., Chambers J. B., Jr Metabolism of the diiodotyrosyl moiety of specifically labeled thyroxines. Endocrinology. 1968 Sep;83(3):489–494. doi: 10.1210/endo-83-3-489. [DOI] [PubMed] [Google Scholar]
  20. Pittman C. S., Read V. H., Chambers J. B., Jr, Nakafuji H. The integrity of the ether linkage during thyroxine metabolism in man. J Clin Invest. 1970 Feb;49(2):373–380. doi: 10.1172/JCI106246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sakurada T., Rudolph M., Fang S. L., Vagenakis A. G., Braverman L. E., Ingbar S. H. Evidence that triiodothyronine and reverse triiodothyronine are sequentially deiodinated in man. J Clin Endocrinol Metab. 1978 Jun;46(6):916–922. doi: 10.1210/jcem-46-6-916. [DOI] [PubMed] [Google Scholar]
  22. Sorimachi K., Cahnmann H. J. A simple synthesis of [3,5-125I]Diiodo-L-thyroxine of high specific activity. Endocrinology. 1977 Oct;101(4):1276–1280. doi: 10.1210/endo-101-4-1276. [DOI] [PubMed] [Google Scholar]
  23. Sorimachi K., Ui N. Ion-exchange chromatographic analysis of iodothyronines. Anal Biochem. 1975 Jul;67(1):157–165. doi: 10.1016/0003-2697(75)90283-3. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Utiger R. D. Serum triiodothyronine in man. Annu Rev Med. 1974;25:289–302. doi: 10.1146/annurev.me.25.020174.001445. [DOI] [PubMed] [Google Scholar]
  26. WYNN J., GIBBS R. Thyroxine degradation. II. Products of thyroxine degradation by rat liver microsomes. J Biol Chem. 1962 Nov;237:3499–3505. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES