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. (Endocrine Reviews 23: 38–89, 2002)

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H(2)O(2) produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins.

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Selenium, the Thyroid, and the Endocrine System

The deiodination of thyroid hormones in extrathyroidal tissues plays an important role in modulating thyroid hormone action. The type II deiodinase (DII) converts thyroxine to the active hormone 3,5,3'-triiodothyronine, and in the rat is expressed in the brain, pituitary gland, and brown adipose tissue (BAT). Complementary DNAs (cDNAs) for the types I and III deiodinases (DI and DIII, respectively) have been isolated and shown to code for selenoproteins. However, information concerning the structure of the mammalian DII remains limited, and the pattern of its expression in human tissues is undefined. We report herein the identification and characterization of rat and human DII cDNAs. Both code for selenoproteins and exhibit limited regions of homology with the DI and DIII. In the rat pituitary and BAT, DII mRNA levels are altered more than 10-fold by changes in the thyroid hormone status of the animal. Northern analysis of RNA derived from human tissues reveals expression of DII transcripts in heart, skeletal muscle, placenta, fetal brain, and several regions of the adult brain. These studies demonstrate that: (a) the rat and human DII are selenoproteins, (b) DII expression in the rat is regulated, at least in part, at the pretranslational level in some tissues, and (c) DII is likely to be of considerable physiologic importance in thyroid hormone economy in the human fetus and adult.

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Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues.

Thyroid hormones control growth, development, differentiation and metabolism in vertebrates. Most of the actions of the active thyroid hormone T3 (3,5,3′-triiodo-l-thyronine) are exerted via ligand-activated nuclear T3 receptors. Activation of the secretory product of the thyroid gland, l-thyroxine (3,3′,5,5′-tetraiodo-l-thyronine), or T4, is catalyzed by two enzymes, iodothyronine-5′-deiodinases type I and type II. Inactivation of T4 and T3 occurs via type III iodothyronine-5-deiodinase and to some extent by type I 5′-deiodinase. Complementary DNAs (cDNAs) encoding the substrate-binding selenocysteine-containing subunits of the deiodinases were cloned, though some controversy still exists on the type II 5′-deiodinase subunits. Characterization of tissue-specific expression patterns indicates that these selenium-dependent enzymes exert tight control on local and systemic availability of active T3. Thus, deiodinases are envisaged as guardians to the gate of thyroid hormone action mediated by T3 receptors.

The deiodinase family: selenoenzymes regulating thyroid hormone availability and action

[12] - Iodothyronine Deiodinases

Selenium deficiency in rats is characterized by elevated serum T4 and decreased serum T3 concentrations, and low liver type I (5'D-I) and brain type II (5'D-II) iodothyronine 5'-deiodinase activities. These findings are partially explained by the demonstration that type I 5'D is a selenoprotein; however, 5'D-II does not contain selenium. Since 5'D-II varies inversely with serum T4 concentrations, and serum T4 is elevated in selenium deficiency, the decreased cerebrocortical 5'D-II activity may be secondary to the increased serum T4 levels. To determine the mechanism(s) by which selenium influences 5'D-II activity, we examined the effects of altered selenium intake on brain 5'D-II levels and enzyme turnover in euthyroid and thyroidectomized rats. Rats were fed a selenium-supplemented or selenium-deficient diet for 5 weeks from weaning; half of the animals were also thyroidectomized 3 weeks before death. Selenium deficiency was confirmed by decreased liver and brain glutathione peroxidase activities. In eut...

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Selenium deficiency and type II 5'-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine