Kinetic evidence suggesting two mechanisms for iodothyronine 5'-deiodination in rat cerebral cortex
01 Aug 1982-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 79, Iss: 16, pp 5080-5084
TL;DR: Evidence was obtained for the existence of two thiol-dependent 5'-deiodinase entities that predominates in tissue from euthyroid and long-term hypothyroid rats, and one of these follows "ping-pong" kinetics with dithiothreitol as the cosubstrate, and is inhibited by propylthiouracil (PrSUra) and iodoacetate.
Abstract: Enzymatic 5'-deiodination of 3,3',5'-triiodothyronine (rT3) and 3,3',5,5'-tetraiodothyronine (thyroxine, T4) was studied in microsomal preparations of rat cerebral cortex. Evidence was obtained for the existence of two thiol-dependent 5'-deiodinase entities. One of these predominates in tissue from euthyroid and long-term hypothyroid rats, is specific for rT3, follows "ping-pong" kinetics with dithiothreitol as the cosubstrate, and is inhibited by propylthiouracil (PrSUra) and iodoacetate. Inhibition by PrSUra is uncompetitive with rT3 and competitive with dithiothreitol. These properties are shared with the 5'-deiodinase activity of liver and kidney. The activity of a second type of 5'-deiodinase is highest in cerebral cortex from short-term hypothyroid rats, prefers T4 to rT3 as the substrate, is insensitive to PrSUra and iodoacetate, and follows "sequential" reaction kinetics. A similar PrSUra-insensitive 5'-deiodinase activity is also found in pituitary but is not detectable in liver and kidney; it seems, therefore, characteristic of tissues in which local T4 to 3,3',5-triiodothyronine (T3) conversion supplies a major portion of the total intracellular T3.
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TL;DR: The goal of this review is to place the exciting advances that have occurred in 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.
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 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)
1,670 citations
TL;DR: In this paper, the effects of persistent polyhalogenated aromatic hydrocarbons (PHAHs) and their metabolites on the thyroid gland were investigated in animals and their offspring.
Abstract: Several classes of environmental contaminants have been claimed or suggested to possess endocrine-disrupting potency, which may result in reproductive problems and developmental disorders. In this paper the focus is on the multiple and interactive mechanisms of interference of persistent polyhalogenated aromatic hydrocarbons (PHAHs) and their metabolites with the thyroid hormone system. Evidence suggests that pure congeners or mixtures of PHAHs directly interfere with the thyroid gland; with thyroid hormone metabolizing enzymes, such as uridine-diphosphate-glucuronyl transferases (UGTs), iodothyronine deiodinases (IDs), and sulfotransferases (SULTs) in liver and brain; and with the plasma transport system of thyroid hormones in experimental animals and their offspring. Changes in thyroid hormone levels in conjunction with high PHAH exposure was also observed in captive as well as free ranging wildlife species and in humans. Maternal exposure to PHAHs during pregnancy resulted in a considerable fetal transfer of hydroxylated PHAHs, which are known to compete with thyroxine (T4) for plasma transthyretin (TTR) binding sites, and thus may be transported to the fetus with those carrier proteins that normally mediate the delivery of T4 to the fetus. Concomitant changes in thyroid hormone concentrations in plasma and in brain tissue were observed in fetal and neonatal stages of development, when sufficient thyroid hormone levels are essential for normal brain development. Alterations in structural and functional neurochemical parameters, such as glial fibrillary acidic protein (GFAP), synaptophysin, calcineurin, and serotonergic neurotransmitters, were observed in the same offspring up to postnatal day 90. In addition, some changes in locomotor and cognitive indices of behavior were observed in rat offspring, following in utero and lactational exposure to PHAHs. Alterations in thyroid hormone levels and subtle changes in neurobehavioral performance were also observed in human infants exposed in utero and through lactation to relatively high levels of PHAHs. Overall these studies indicate that persistent PHAHs can disrupt the thyroid hormone system at a multitude of interaction sites, which may have a profound impact on normal brain development in experimental animals, wildlife species, and human infants.
596 citations
TL;DR: In patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine may improve mood and neuropsychological function; this finding suggests a specific effect of the triiod Timothyronine normally secreted by the thyroid gland.
Abstract: Background Patients with hypothyroidism are usually treated with thyroxine (levothyroxine) only, although both thyroxine and triiodothyronine are secreted by the normal thyroid gland. Whether thyroid secretion of triiodothyronine is physiologically important is unknown. Methods We compared the effects of thyroxine alone with those of thyroxine plus triiodothyronine (liothyronine) in 33 patients with hypothyroidism. Each patient was studied for two five-week periods. During one period, the patient received his or her usual dose of thyroxine. During the other, the patient received a regimen in which 50 μg of the usual dose of thyroxine was replaced by 12.5 μg of triiodothyronine. The order in which each patient received the two treatments was randomized. Biochemical, physiologic, and psychological tests were performed at the end of each treatment period. Results The patients had lower serum free and total thyroxine concentrations and higher serum total triiodothyronine concentrations after treatment with th...
448 citations
TL;DR: It is reported here that both noradrenaline and cold exposure increase BAT 5′D-II through α1-adrenergic receptors, whereas depletion of catecholamines with α-methyl-p-tyrosine (MPT) prevents the effect of cold but not that of nor adrenaline.
Abstract: There are several mechanisms by which homeothermic animals increase heat production, including shivering, sympathetic nervous system activation and stimulation of thyroid hormone secretion. Studies in rats have shown that increased sympathetic activity causes increased heat production in brown adipose tissue (BAT) after cold exposure or food ingestion1–3. Acute cold exposure also increases circulating thyroid hormones4 which in turn stimulate cellular metabolism through induction5 of various enzymes. Most metabolic effects of thyroxine (T4) are thought to be due to the triiodothyronine (T3) which is produced from T4 by a process of 5′ monodeiodination. There are two enzymes responsible for this reaction6–8: type I, or propylthiouracil (PTU)-sensitive iodothyronine deiodinase (5′D-I), which is reduced in hypothyroidism, stimulated in hyperthyroidism and probably provides most of the circulating T3 in the adult rat9. Type II 5′-deiodinase (5′D-II) is characteristic of brain and pituitary, is increased by thyroidectomy, is not inhibited by PTU and provides 50–80% of the intraceUular T3 in these two tissues. Recently, 5′D-II activity was identified in interscapular BAT10. As the sympathetic nervous system influences the metabolic activation of BAT, we have studied the effects of noradrenaline and acute cold exposure on BAT 5′D-II. We report here that both noradrenaline and cold exposure increase BAT 5′D-II through α1-adrenergic receptors, whereas depletion of catecholamines with α-methyl-p-tyrosine (MPT) prevents the effect of cold but not that of noradrenaline. These results suggest that the sympathetic nervous system may increase T3 production in rats by stimulating BAT 5′D-II. By increasing metabolic rate, this rise in T3 would enhance the thermogenic response to sympathetic stimulation.
375 citations
TL;DR: The demonstration that all three deiodinase isoforms contain at their active site the uncommon amino acid selenocysteine which is of critical importance to their catalytic activity has provided important insights into the structural characteristics of this family of enzymes.
Abstract: The realization some forty years ago that several iodothyronine compounds are present in the circulation suggested that deiodination occurs in various tissues. Subsequently, deiodination was indeed...
335 citations