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Endocrine Reviews 23 (1): 38-89
Copyright © 2002 by The Endocrine Society

Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases

Antonio C. Bianco, Domenico Salvatore, Balázs Gereben, Marla J. Berry and P. Reed Larsen

Thyroid Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (A.C.B., M.J.B., P.R.L.), Boston, Massachusetts 02115; Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Universita’ Federico II (D.S.), 80131 Naples, Italy; Institute of Experimental Medicine, Hungarian Academy of Sciences (B.G.), Budapest, H-1083 Hungary

Correspondence: Address all correspondence and requests for reprints to: P. Reed Larsen, M.D., Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine Building, Room 550, Boston, Massachusetts 02115. E-mail: rlarsen{at}rics.bwh.harvard.edu

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.




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V. A. Galton, E. T. Wood, E. A. St. Germain, C.-A. Withrow, G. Aldrich, G. M. St. Germain, A. S. Clark, and D. L. St. Germain
Thyroid Hormone Homeostasis and Action in the Type 2 Deiodinase-Deficient Rodent Brain during Development
Endocrinology, July 1, 2007; 148(7): 3080 - 3088.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. L. Chik, M. T. Wloka, D. M. Price, and A. K. Ho
The Role of Repressor Proteins in the Adrenergic Induction of Type II Iodothyronine Deiodinase in Rat Pinealocytes
Endocrinology, July 1, 2007; 148(7): 3523 - 3531.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
M. S Wagner, S. M Wajner, J. M Dora, and A. L. Maia
Regulation of Dio2 gene expression by thyroid hormones in normal and type 1 deiodinase-deficient C3H mice
J. Endocrinol., June 1, 2007; 193(3): 435 - 444.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. Jansen, E. C. H. Friesema, M. H. A. Kester, C. Milici, M. Reeser, A. Gruters, T. G. Barrett, E. E. Mancilla, J. Svensson, J.-L. Wemeau, et al.
Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2378 - 2381.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
P. Laurberg, H. Vestergaard, S. Nielsen, S. E. Christensen, T. Seefeldt, K. Helleberg, and K. M. Pedersen
Sources of Circulating 3,5,3'-Triiodothyronine in Hyperthyroidism Estimated after Blocking of Type 1 and Type 2 Iodothyronine Deiodinases
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2149 - 2156.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. Suzuki, N. Suzuki, J.-i. Mori, A. Oshima, S. Usami, and K. Hashizume
{micro}-Crystallin as an Intracellular 3,5,3'-Triiodothyronine Holder in Vivo
Mol. Endocrinol., April 1, 2007; 21(4): 885 - 894.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
Y. Kanou, A. Hishinuma, K. Tsunekawa, K. Seki, Y. Mizuno, H. Fujisawa, T. Imai, Y. Miura, T. Nagasaka, C. Yamada, et al.
Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity
J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1451 - 1457.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. A. Christoffolete, R. Arrojo e Drigo, F. Gazoni, S. M. Tente, V. Goncalves, B. S. Amorim, P. R. Larsen, A. C. Bianco, and A. M. Zavacki
Mice with Impaired Extrathyroidal Thyroxine to 3,5,3'-Triiodothyronine Conversion Maintain Normal Serum 3,5,3'-Triiodothyronine Concentrations
Endocrinology, March 1, 2007; 148(3): 954 - 960.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
O. Gumieniak, T. S. Perlstein, J. S. Williams, P. N. Hopkins, N. J. Brown, B. A. Raby, and G. H. Williams
Ala92 Type 2 Deiodinase Allele Increases Risk for the Development of Hypertension
Hypertension, March 1, 2007; 49(3): 461 - 466.
[Abstract] [Full Text] [PDF]

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 Am. J. Clin. Nutr.Home page
E. Ortega, N. Pannacciulli, C. Bogardus, and J. Krakoff
Plasma concentrations of free triiodothyronine predict weight change in euthyroid persons
Am. J. Clinical Nutrition, February 1, 2007; 85(2): 440 - 445.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
F. J. de Jong, R. P. Peeters, T. den Heijer, W. M. van der Deure, A. Hofman, A. G. Uitterlinden, T. J. Visser, and M. M. B. Breteler
The Association of Polymorphisms in the Type 1 and 2 Deiodinase Genes with Circulating Thyroid Hormone Parameters and Atrophy of the Medial Temporal Lobe
J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 636 - 640.
[Abstract] [Full Text] [PDF]

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 Annals of Clinical & Laboratory ScienceHome page
A. E. Balazs, I. Athanassaki, S. K. Gunn, N. Tatevian, S. A. Huang, M. W. Haymond, and L. P. Karaviti
Rapid Resolution of Consumptive Hypothyroidism in a Child with Hepatic Hemangioendothelioma Following Liver Transplantation
Ann. Clin. Lab. Sci., January 1, 2007; 37(3): 280 - 284.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
M. P Marassi, R. S Fortunato, A. C M. da Silva, V. S Pereira, D. P Carvalho, D. Rosenthal, and V. M C. da Costa
Sexual dimorphism in thyroid function and type 1 iodothyronine deiodinase activity in pre-pubertal and adult rats
J. Endocrinol., January 1, 2007; 192(1): 121 - 130.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
N. Grarup, M. K. Andersen, C. H. Andreasen, A. Albrechtsen, K. Borch-Johnsen, T. Jorgensen, J. Auwerx, O. Schmitz, T. Hansen, and O. Pedersen
Studies of the Common DIO2 Thr92Ala Polymorphism and Metabolic Phenotypes in 7342 Danish White Subjects
J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 363 - 366.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. H. A. Kester, G. G. J. M. Kuiper, R. Versteeg, and T. J. Visser
Regulation of Type III Iodothyronine Deiodinase Expression in Human Cell Lines
Endocrinology, December 1, 2006; 147(12): 5845 - 5854.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
R. P Peeters, W. M van der Deure, and T. J Visser
Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases.
Eur. J. Endocrinol., November 1, 2006; 155(5): 655 - 662.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
E. C. H. Friesema, G. G. J. M. Kuiper, J. Jansen, T. J. Visser, and M. H. A. Kester
Thyroid Hormone Transport by the Human Monocarboxylate Transporter 8 and Its Rate-Limiting Role in Intracellular Metabolism
Mol. Endocrinol., November 1, 2006; 20(11): 2761 - 2772.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Zeold, L. Pormuller, M. Dentice, J. W. Harney, C. Curcio-Morelli, S. M. Tente, A. C. Bianco, and B. Gereben
Metabolic Instability of Type 2 Deiodinase Is Transferable To Stable Proteins Independently of Subcellular Localization
J. Biol. Chem., October 20, 2006; 281(42): 31538 - 31543.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. J. De Blasio, K. L. Gatford, J. S. Robinson, and J. A. Owens
Placental restriction alters circulating thyroid hormone in the young lamb postnatally
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1016 - R1024.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
X. Ding, K. Lichti, I. Kim, F. J. Gonzalez, and J. L. Staudinger
Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor {alpha}, and the Coactivator Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha}
J. Biol. Chem., September 8, 2006; 281(36): 26540 - 26551.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
J. Bernal
Role of Monocarboxylate Anion Transporter 8 (MCT8) in Thyroid Hormone Transport: Answers from Mice.
Endocrinology, September 1, 2006; 147(9): 4034 - 4035.
[Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
P. Saravanan, T. J. Visser, and C. M. Dayan
Psychological Well-Being Correlates with Free Thyroxine But Not Free 3,5,3'-Triiodothyronine Levels in Patients on Thyroid Hormone Replacement
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3389 - 3393.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. M. Dumitrescu, X.-H. Liao, R. E. Weiss, K. Millen, and S. Refetoff
Tissue-Specific Thyroid Hormone Deprivation and Excess in Monocarboxylate Transporter (Mct) 8-Deficient Mice
Endocrinology, September 1, 2006; 147(9): 4036 - 4043.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. Zeold, M. Doleschall, M. C. Haffner, L. P. Capelo, J. Menyhert, Z. Liposits, W. S. da Silva, A. C. Bianco, I. Kacskovics, C. Fekete, et al.
Characterization of the Nuclear Factor-{kappa}B Responsiveness of the Human dio2 Gene
Endocrinology, September 1, 2006; 147(9): 4419 - 4429.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
B. Anguiano, A. Lopez, G. Delgado, C. Romero, and C. Aceves
Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones.
J. Endocrinol., August 1, 2006; 190(2): 363 - 371.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
P. H Bisschop, A. W Toorians, E. Endert, W. M Wiersinga, L. J Gooren, and E. Fliers
The effects of sex-steroid administration on the pituitary-thyroid axis in transsexuals.
Eur. J. Endocrinol., July 1, 2006; 155(1): 11 - 16.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
G. G. J. M. Kuiper, W. Klootwijk, G. Morvan Dubois, O. Destree, V. M. Darras, S. Van der Geyten, B. Demeneix, and T. J. Visser
Characterization of Recombinant Xenopus laevis Type I Iodothyronine Deiodinase: Substitution of a Proline Residue in the Catalytic Center by Serine (Pro132Ser) Restores Sensitivity to 6-Propyl-2-Thiouracil
Endocrinology, July 1, 2006; 147(7): 3519 - 3529.
[Abstract] [Full Text] [PDF]

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 J Mol EndocrinolHome page
M. Nygard, N. Becker, B. Demeneix, K. Pettersson, and M. Bondesson
Thyroid hormone-mediated negative transcriptional regulation of Necdin expression.
J. Mol. Endocrinol., June 1, 2006; 36(3): 517 - 530.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
J. P Brouwer, B. C Appelhof, R. P Peeters, W. J G Hoogendijk, J. Huyser, A. H Schene, J. G P Tijssen, R. Van Dyck, T. J Visser, W. M Wiersinga, et al.
Thyrotropin, but not a polymorphism in type II deiodinase, predicts response to paroxetine in major depression.
Eur. J. Endocrinol., June 1, 2006; 154(6): 819 - 825.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
A. G. Trentin
Thyroid hormone and astrocyte morphogenesis.
J. Endocrinol., May 1, 2006; 189(2): 189 - 197.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
T. J. Visser
The elemental importance of sufficient iodine intake: a trace is not enough.
Endocrinology, May 1, 2006; 147(5): 2095 - 2097.
[Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. R. Roberts, M. Srinivas, D. Forrest, G. Morreale de Escobar, and T. A. Reh
Making the gradient: Thyroid hormone regulates cone opsin expression in the developing mouse retina
PNAS, April 18, 2006; 103(16): 6218 - 6223.
[Abstract] [Full Text] [PDF]

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 Physiol. Rev.Home page
J. E. Silva
Thermogenic Mechanisms and Their Hormonal Regulation
Physiol Rev, April 1, 2006; 86(2): 435 - 464.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. A. Christoffolete, R. Ribeiro, P. Singru, C. Fekete, W. S. da Silva, D. F. Gordon, S. A. Huang, A. Crescenzi, J. W. Harney, E. C. Ridgway, et al.
Atypical Expression of Type 2 Iodothyronine Deiodinase in Thyrotrophs Explains the Thyroxine-Mediated Pituitary Thyrotropin Feedback Mechanism
Endocrinology, April 1, 2006; 147(4): 1735 - 1743.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
A. Alkemade, E. C Friesema, G. G Kuiper, W. M Wiersinga, D. F Swaab, T. J Visser, and E. Fliers
Novel neuroanatomical pathways for thyroid hormone action in the human anterior pituitary.
Eur. J. Endocrinol., March 1, 2006; 154(3): 491 - 500.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
I. del Barco Barrantes, A. Montero-Pedrazuela, A. Guadano-Ferraz, M.-J. Obregon, R. Martinez de Mena, V. Gailus-Durner, H. Fuchs, T. J. Franz, S. Kalaydjiev, M. Klempt, et al.
Generation and Characterization of dickkopf3 Mutant Mice.
Mol. Cell. Biol., March 1, 2006; 26(6): 2317 - 2326.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
V. Sharma, W. R. Hays, W. M. Wood, U. Pugazhenthi, D. L. St. Germain, A. C. Bianco, W. Krezel, P. Chambon, and B. R. Haugen
Effects of Rexinoids on Thyrotrope Function and the Hypothalamic-Pituitary-Thyroid Axis
Endocrinology, March 1, 2006; 147(3): 1438 - 1451.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
L. Schomburg, C. Riese, M. Michaelis, E. Griebert, M. O. Klein, R. Sapin, U. Schweizer, and J. Kohrle
Synthesis and Metabolism of Thyroid Hormones Is Preferentially Maintained in Selenium-Deficient Transgenic Mice
Endocrinology, March 1, 2006; 147(3): 1306 - 1313.
[Abstract] [Full Text] [PDF]


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