The DOI matches its Crossref record; 507 of the 531 references it cites were found in a registry or an index.
Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases
Abstract
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 T(3) 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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In the citing paper
“Due to alterations in rates of local deiodination in tissues, thyroid hormone signaling can change irrespective of serum hormonal concentrations (3, 5).”
From Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism? (2019) · cites this paper as [3]
In the citing paper
“Of note, the D1 gene is upregulated by T3, and thus in hyperthyroidism the proportion of circulating T3 arising from the D1 pathway is significantly increased (11).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [11]
In the citing paper
“A third deiodinase, type 3 deiodinase (D3) participates in the clearance of both serum T4 and T3 (11).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [11]
In the citing paper
“The in-sufficient peripheral T3 production cannot be appropriately corrected by increasing L-T4 dose, because the inhibitory effect of elevated T4 on D2 [28,30,69] will end up increasing the imbalance of serum free T4 to free T3 ratio [67] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [69]
In the citing paper
“with the thyroid producing only ∼5 mcg T3”
From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [32]
In the citing paper
“an additional ∼25 mcg T3 is produced daily outside of the thyroid parenchyma via T4 deiodination (32).”
From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [32]
In the citing paper
“The daily T3 production in a 70-kg healthy adult is ∼30 mcg”
From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [32]
In the citing paper
“FT3 measurement has somewhat limited utility, however, in the diagnosis of hypothyroidism, since FT3 values often fall in the normal range as a result of hyperstimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of deiodinase D2”
From Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report (2017) · cites this paper as [25]
In the citing paper
“Similarly, deiodinases in central and peripheral tissues are also regulated differently, enhancing T3 conversion and providing a differentiated mechanism for oversensitively responding to changes in FT4 in the feedback loop (55–63).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [57]
In the citing paper
“T3 supply is locally controlled by several mechanisms, such as active thyroid hormone uptake, tissue-specific expression and activity of two distinct types of deiodinases converting T3 from T4, and thyroid hormone inactivation by deiodination or degradation by sulfatation, deamination, or glucoronidation (57–66).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [57]
In the citing paper
“The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism (57–64).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [57]
In the citing paper
“The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism (57–64).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [57]
In the citing paper
“The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism (57–64).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [57]
In the citing paper
“the conversion of T 4 to T 3 in the brain is catalyzed by D2 (94)”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [94]
In the citing paper
“In the cortex, for example, hypothyroidism up-regulates D2 activity to produce more T 3 , whereas hyperthyroidism down-regulates D2 activity (94)”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [94]
In the citing paper
“Primarily, deiodination of T4’s outer ring by type 2 deiodinase (DIO2) gives liothyronine (L-tri-iodothyronine or T3, the main biologically active metabolite), and deiodination of the inner ring by type 1 or type 3 deiodinases (DIO1 or DIO3) gives the biologically inactive reverse T3 (rT3) [ 21 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [21]
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Metadata
- Authors
- Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R.
- Affiliations
- Brigham and Women's Hospital (US)
- Federico II University Hospital (IT)
- Institute of Experimental Medicine, Hungarian Academy of Sciences (B.G.), Budapest, H-1083 Hungary
- Corresponding author
- Larsen, P. Reed
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2002-02-01
- Volume
- 23
- Issue
- 1
- Pages
- 38-89
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- OpenAlex
- W2104878795
- Cited by
- 1,853
- References
- 531
- Citations by year
- 2026: 32 · 2025: 59 · 2024: 44 · 2023: 58 · 2022: 88 · 2021: 83 · 2020: 85 · 2019: 81 · 2018: 69 · 2017: 84 · 2016: 82 · 2015: 90 · 2014: 71 · 2013: 69 · 2012: 85
- FWCI
- 12.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK044128, DK36256, DK 58538, DK-44128, R01DK036256, T32DK007529, DK-07529)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Chemical Analysis and Environmental Impact
- Keywords
- iodothyronine deiodinase, selenoprotein biosynthesis, type 2 deiodinase, type 3 deiodinase, type I deiodinase, thyroid hormone metabolism, structure-activity relationship
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Humans, Iodide Peroxidase, Molecular Sequence Data, Polymorphism, Genetic, Proteins, Protein Biosynthesis, Sequence Homology, Amino Acid, Selenoproteins
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