Deiodinases control local cellular and systemic thyroid hormone availability

Köhrle, Josef; Frädrich, Caroline

doi:10.1016/j.freeradbiomed.2022.09.024

Cited by 53 publications

(38 citation statements)

References 234 publications

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“…Similarly, a hierarchy is also found between selenoproteins with, e.g., Gpx4, Dios and some of the selenoproteins assisting with protein folding. Intracellular DIOs are crucial for the pre-receptor control of local T3-ligand availability to the T3 receptors, which act as T3-ligand-dependent transcription factors modulating the expression of TH-responsive genes in target cells of TH action [ 10 ].…”

Section: Selenoproteinsmentioning

confidence: 99%

“…The three deiodinase (DIO; EC:1.21.99.4, EC:1.21.99.4) enzymes, key to the local cellular activation and the inactivation of TH T 4 and T 3 in the thyroid gland and target tissues of TH action, were identified 30 years ago as the second selenoprotein family after glutathione peroxidases [ 7 ]. Glutathione peroxidases (GPx) defend the thyroid against continuous H 2 O 2 production [ 8 ], together with the thioredoxin reductase (TXNRD) families [ 9 ], as well as the various selenoproteins involved in cellular redox controls and the quality control of the biosynthesis of thyroglobulin (TG), the major product of thyroid follicles, an essential protein for TH biosynthesis, storage and secretion [ 10 ]. Se deficiency impairs thyroid function and TH production and secretion and various studies test whether and which thyroid-hormone-related disorders might be prevented or treated by (adjuvant) nutritional Se supply or Se-containing drugs [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Köhrle

2023

IJMS

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The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H2O2-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus–pituitary–thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as ‘thyroxisome’ at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

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Section: Selenoproteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Köhrle

2023

IJMS

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“…Type 1 (D1) and type 3 deiodinases (D3) convert thyroxine (T4) to rT3 by inner ring deiodination. D1 is positively regulated by T3, while D3 by T3 and Hypoxia-inducible factor 1α (HIF-1α) (34). As a consequence, rT3 is reduced in hypothyroid patients and increased in those affected with NTIs.…”

Section: Critical Illnessesmentioning

confidence: 99%

Unusual causes of hyperthyrotropinemia and differential diagnosis of primary hypothyroidism: a revised diagnostic flowchart

Campi

Grassi

Vigone

et al. 2023

European Thyroid Journal

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The clinical consequences of primary hypothyroidism include cardiovascular morbidity, increased mortality and poor quality of life, therefore guidelines endorsed by several Scientific Societies recommend measuring circulating TSH in patients at risk. The assessment of serum TSH levels is also deemed to be the most robust and accurate biomarker during the management of replacement therapy in patients with a previous diagnosis of primary hypothyroidism. In line with a reflex TSH laboratory strategy, free T4 is measured only if the TSH falls outside specific cut-offs, in order to streamline investigations and save unjustified costs. This serum TSH-based approach to both diagnosis and monitoring has been widely accepted by several national and local health services, nevertheless false negative or positive TSH testing may occur leading to inappropriate management or treatment. This review aims to describe several infrequent causes of increased circulating TSH, including analytical interference, resistance to TSH, consumptive hypothyroidism, and refractoriness to levothyroxine replacement treatment. We propose a clinical flow-chart to aid correct recognition of these various conditions, that represent important potential pitfalls in the diagnosis and treatment of primary hypothyroidism.

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“…For instance, it is recognized that many potential TH system disruptors can act via a number of different mechanisms that are not detected by analyzing the thyroid gland itself, nor by measuring systemic levels of the THs triiodothyronine (T3) and thyroxine (T4) ( Noyes et al, 2019 ; Gilbert et al, 2020 ). This is because changes in, for instance, deiodinase activity or membrane transport of THs, will not necessarily affect circulating levels of TH, but could still have a large impact on TH availability and action in target tissues ( Landers and Richard, 2017 ; Gilbert et al, 2020 ; Köhrle and Frädrich, 2022 ). Lastly, TH-mediated adverse effects in target tissues peripheral to the thyroid gland are not addressed by current test methods, including TH-mediated developmental neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

New approach methods to improve human health risk assessment of thyroid hormone system disruption–a PARC project

Ramhøj,

Axelstad,

Baert

et al. 2023

Front. Toxicol.

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Current test strategies to identify thyroid hormone (TH) system disruptors are inadequate for conducting robust chemical risk assessment required for regulation. The tests rely heavily on histopathological changes in rodent thyroid glands or measuring changes in systemic TH levels, but they lack specific new approach methodologies (NAMs) that can adequately detect TH-mediated effects. Such alternative test methods are needed to infer a causal relationship between molecular initiating events and adverse outcomes such as perturbed brain development. Although some NAMs that are relevant for TH system disruption are available–and are currently in the process of regulatory validation–there is still a need to develop more extensive alternative test batteries to cover the range of potential key events along the causal pathway between initial chemical disruption and adverse outcomes in humans. This project, funded under the Partnership for the Assessment of Risk from Chemicals (PARC) initiative, aims to facilitate the development of NAMs that are specific for TH system disruption by characterizing in vivo mechanisms of action that can be targeted by in embryo/in vitro/in silico/in chemico testing strategies. We will develop and improve human-relevant in vitro test systems to capture effects on important areas of the TH system. Furthermore, we will elaborate on important species differences in TH system disruption by incorporating non-mammalian vertebrate test species alongside classical laboratory rat species and human-derived in vitro assays.

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Deiodinases control local cellular and systemic thyroid hormone availability

Cited by 53 publications

References 234 publications

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Unusual causes of hyperthyrotropinemia and differential diagnosis of primary hypothyroidism: a revised diagnostic flowchart

New approach methods to improve human health risk assessment of thyroid hormone system disruption–a PARC project

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