Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.

Development and tissue-specific deiodination of thyroid hormone leads to both activation of the prohormone thyroxine to the thyromimetically active T3 as well as to inactivation of T3 and its conjugates or inactivation of T4 to yield potential regulatory active rT3. At least three deiodinase isoenzymes have so far been characterized and cloned, and the deiodinase isozymes represent a new family of eukaryotic selenoproteins for which an enzyme function could be assigned. Selenium status apparently regulates the expression of these deiodinase isozymes to different extent indicating that a hierarchy of selenium incorporation exists for those enzymes. Currently, it appears that selenium deficiency does not affect expression of type II 5'-deiodinase or 5-deiodinase to a marked extent in vivo whereas type I 5'-deiodinase at least in liver and kidney is reduced in severe selenium deficiency. However, daily selenium intake in normal mideuropeans already saturates the requirement for the expression of the deiodinase isoenzymes. So far, only reduced expression of 5'-D I and decreased T 3 production has been observed in specific diets such as for PKU or in cystic fibrosis, where transport of ions (iodide, selenite?) might be affected. Further alterations of T3 production by 5'-D I activity are observed under the conditions of the low T3 syndrome, which comprise a broad spectrum of clinical disorders from carbohydrate withdrawal to intensive care patients. It is not yet clear if selenium supplementation or T3 treatment is beneficial to these patients. The marked tissue-specificity of expression of the deiodinases requires more detailed examinations on the relation between these enzymes and the expression of thyroid hormone action, which is mediated by the nuclear T3 receptor family or receptors and signal transduction molecules in the mitochondria, plasma membrane, or cytoskeleton. The location of the deiodinase enzymes either at the inner side of the plasma membrane or the cytosolic side of the endoplasmic reticulum positions these enzymes to a strategically important location enabling them to act as gate-keepers to the nuclear receptors. Similar to other enzymes involved in the activation or inactivation of compounds with hormone or signalling function, the deiodinases are key elements in the intracrine regulation of hormone activation in target tissues or inactivation in non-target tissues. Therefore, a detailed molecular, cell biological and physiological analysis of the function, regulation and gene structure of these enzymes is required before a development of tissue- or enzyme-specific pharmacological intervention is possible. Nevertheless, first data indicate that reduced 5'-deiodinase type I expression in tumor tissues can be re-induced by treatment with retinoids at least in follicular thyroid carcinoma. Further studies are needed to prove that retinoids might be a useful therapeutic tool for re-differentiation therapy of thyroid carcinoma which are inaccessible to surgical intervention or lack radio-iodide uptake and storage. The important function and regio- and cell-specific expression of deiodinase isozymes in the central nervous system is far from being understood. Current first evidence suggests a close interaction between thyroid hormone deiodination, thyroid hormone concentration, and expression of thyroid hormone responsive genes in the adult brain as well as tight regulation and interaction between thyroid hormone metabolism and neurotransmitter synthesis release and action.