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PubMedDate not supplied

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism.

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T4) to the more metabolically active 3,3'-5 triiodothyronine (T3). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [125I]N-bromoacetyl reverse triiodothyronine, is also labeled with 75Se by in vivo treatment of rats with 75Se-Na2SeO3. Thus, the type I iodothyronine 5'-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.

Animals↗
PubMed1984

Women on thyroid hormone therapy: pregnancy course, fetal outcome, and amniotic fluid thyroid hormone level.

Thirty-four hypothyroid women on thyroid hormone substitution were followed through 37 pregnancies, and 16 women having previous surgery for thyroid carcinoma and thereafter placed on suppressive thyroxine treatment were followed through 19 pregnancies. The thyroxine treatment needed readjustment in 13 pregnancies (23%) to maintain euthyroidism. At delivery, the maternal free thyroxine index was 126 nmol/L in the group of patients treated for hypothyroidism and 146 nmol/L in the patients with treated thyroid carcinoma. The amniotic fluid thyroxine level in normal pregnancies was 6.7 nmol/L, in hypothyroid patients 6.7 nmol/L, and in patients with thyroid carcinoma 5.6 nmol/L. The amniotic fluid reverse triiodothyronine level in normal pregnancies was 0.51 nmol/L, in hypothyroid patients 0.66 nmol/L, and in patients with thyroid carcinoma 0.70 nmol/L. All infants were euthyroid.

Adenocarcinoma↗
PubMed1995

Interdependence of corticosterone and thyroid hormones in toad larvae (Bufo boreas). II. Regulation of corticosterone and thyroid hormones.

Typically, the role of corticosterone(B) in metamorphosis is considered secondary to that of thyroid hormone, with B having only enhancing effects. In the current study, we demonstrate that the relationship between the thyroid hormones and B is much more complex and that thyroxine (T4) may depend on B for some of its functions. Tadpoles of the western toad (Bufo boreas) were treated with various combinations of corticosterone (B), thyroxine (T4), triiodothyronine (T3), a goitrogen (thiourea; Thio), and a corticoid synthesis inhibitor (metyrapone; MTP). Hormones were extracted from individual tadpoles and whole-body hormone levels determined by radioimmunoassay. B-treatment decreased the ratio of T4 to T3, suggesting that B increased the conversion of endogenous T4 to T3. In addition, B-treatment in combination with T4 resulted in high whole body-levels of T3. B also caused a decrease in whole body-thyroid hormone levels (T4 and T3), suggesting negative feedback on the hypothalamo-pituitary-thyroid axis and T3 had a similar effect, decreasing whole body-T4 levels. T4-treatment, but not T3, increased whole body-B levels and MTP-treatment in combination with T4 prevented the stimulatory effect of T4 on B production. MTP-treatment alone blocked all steroid metabolism of [3H]progesterone by the inter-renal in vitro, and lowered whole body-B levels three-fold in vivo. Thio-treatment reduced thyroid hormone levels and also resulted in decreased B. Finally, we suggest that these results demonstrate a system in which T4 may regulate its own potency: increasing T4 stimulates B production, which increases the conversion of T4 to its more active form T3.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

Three novel mutations of thyroid hormone receptor beta gene in unrelated patients with resistance to thyroid hormone: two mutations of the same codon (H435L and H435Q) produce separate subtypes of resistance.

We report three novel mutations of the thyroid hormone receptor beta (TR beta) gene in three unrelated Japanese patients with resistance to thyroid hormone (RTH). Patients A and B exhibited generalized resistance phenotype, while patient C displayed more pituitary-selective unresponsiveness. Direct sequencing of TR beta gene exon 10 disclosed novel point mutations in all three patients. A Phe to Ile (TTC-->ATC) substitution at codon 451, a His to Leu (CAT-->CTT) substitution at codon 435, and a His to Gln (CAT-->CAA) substitution at codon 435 were identified in patients A, B, and C, respectively. Sequencing of TR beta gene exons 5-9 as well as TR alpha gene exons 4-9 failed to detect any additional mutations. All three patients were heterozygous for respective mutations. The unaffected parents of patients A and B, having normal thyroid function, possessed no mutations of TR beta gene exon 10, indicating that the F451I and H435L mutations occurred de novo. The F451I mutation is located near the most frequent mutation site in the ligand 2 subdomain. The identical codon mutations H435L and H435Q, which lie at the extreme carboxyl-terminus of the dimerization subdomain near the 9th heptad, were found in clinically different subtypes of RTH: patient B with generalized resistance and patient C with pituitary-selective resistance, respectively. The mutations broaden the growing catalogue of the TR beta gene mutations that could cause different phenotypes, despite the defects at the same codon.

Adult↗
PubMed2001

Critical role for thyroid hormone receptor beta2 in the regulation of paraventricular thyrotropin-releasing hormone neurons.

Thyroid hormone thyroxine (T(4)) and tri-iodothyronine (T(3)) production is regulated by feedback inhibition of thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) synthesis in the pituitary and hypothalamus when T(3) binds to thyroid hormone receptors (TRs) interacting with the promoters of the genes for the TSH subunit and TRH. All of the TR isoforms likely participate in the negative regulation of TSH production in vivo, but the identity of the specific TR isoforms that negatively regulate TRH production are less clear. To clarify the role of the TR-beta2 isoform in the regulation of TRH gene expression in the hypothalamic paraventricular nucleus, we examined preprothyrotropin-releasing hormone (prepro-TRH) expression in mice lacking the TR-beta2 isoform under basal conditions, after the induction of hypothyroidism with propylthiouracil, and in response to T(3) administration. Prepro-TRH expression was increased in hypothyroid wild-type mice and markedly suppressed after T(3) administration. In contrast, basal TRH expression was increased in TR-beta2-null mice to levels seen in hypothyroid wild-type mice and did not change significantly in response to induction of hypothyroidism or T(3) treatment. However, the suppression of TRH mRNA expression in response to leptin reduction during fasting was preserved in TR-beta2-null mice. Thus TR-beta2 is the key TR isoform responsible for T(3)-mediated negative-feedback regulation by hypophysiotropic TRH neurons.

Animals↗
PubMed2004

Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in liver, heart and kidney.

To assess interference with endocrine regulation of the thyroid axis, rats (female, ovariectomised) were treated for 12 weeks with the suspected endocrine active compounds (EAC) or endocrine disrupters (ED) 4-nonylphenol (NP), octyl-methoxycinnamate (OMC) and 4-methylbenzylidene-camphor (4-MBC) as well as 17beta-estradiol (E2) and 5alpha-androstane-3beta,17beta-diol (Adiol) on the background of a soy-free or soy-containing diet, and endpoints relevant for regulation via the thyroid axis were measured. Thyrotropin (TSH) and thyroid hormone (T4, T3) serum levels were altered, but not in a way consistent with known mechanisms of feedback regulation of the thyroid axis. In the liver, malic enzyme (ME) activity was significantly increased by E2 and Adiol, slightly by OMC and MBC and decreased by soy, whereas type I 5'-deiodinase (5'DI) was decreased by all treatments. This may be due rather to the estrogenic effect of the ED, as there is no obvious correlation with T4 or T3 serum levels. None of the substances inhibited thyroid peroxidase (TPO) in vitro, except for NP. In general, several endocrine active compounds disrupt the endocrine feedback regulation of the thyroid axis. However, there was no uniform, obvious pattern in the effects of those ED tested, but each compound elicited its own spectrum of alterations, arguing for multiple targets of interference with the complex network of thyroid hormone action and metabolism.

Animals↗
PubMed1998

Thyroid hormone response elements differentially modulate the interactions of thyroid hormone receptors with two receptor binding domains in the steroid receptor coactivator-1.

Ligand-dependent transcriptional activation by nuclear receptors is mediated by interactions with coactivators. Recently, a consensus interaction motif (LXXLL) has been identified in a number of coactivators such as steroid receptor coactivator-1 (SRC-1). SRC-1 contains three such motifs in the central (nuclear receptor binding domain-1, NBD-1) and a single one in the C-terminal (NBD-2) regions. To define the nature and role of the two NBDs in SRC-1, interaction studies between the two NBDs and thyroid hormone receptor (TR) were performed. Although NBD-1 and NBD-2 showed similar ligand- and AF-2-dependent interactions with TR in solution, these two NBDs possessed distinct interaction properties with TR when TR is bound to a thyroid hormone-response element (TRE). Both in vitro and in vivo interaction studies demonstrate that NBD-1, but not NBD-2, exhibits ligand-dependent interaction with TR in the presence of TREs. In addition, a natural isoform of SRC-1, SRC-1E, which lacks NBD-2, preserved TR as well as progesterone receptor-mediated coactivator function on reporter gene expression. Finally, we found that NBD-1 failed to interact with a TR and retinoid X receptor heterodimer complex on a transcriptionally inactive direct repeat +4 TRE in electrophoretic mobility shift assays. These observations indicate that DNA-induced, as well as ligand-induced, conformational change(s) of TR may influence the nature of its binding to SRC-1, and that the two NBDs of SRC-1 may play different roles to regulate ligand-dependent transactivation of TRs.

Animals↗
PubMed1991

Difference in the susceptibility of two phenobarbital-inducible forms, P450IIB1 and P450IIB2, to thyroid hormone- and growth hormone-induced suppression in rat liver: phenobarbital-inducible P450IIB2 suppression by thyroid hormone acting directly, but not through the pituitary system.

Suppression of two major phenobarbital-inducible cytochrome P-450s, P450IIB1 and P450IIB2, by thyroid hormone was studied and compared with growth hormone (GH)-induced suppression in rats in vivo and hepatocytes in primary culture in vitro. Treatment of adult male rats with 50 micrograms/kg triiodothyronine (T3) reduced the constitutively expressed amounts of P450IIB1 (up to 1 pmol/mg of protein) and P450IIB2 (2-5 pmol/mg of protein) to 42% and 3% of their levels in nontreated controls. Thyroidectomy increased the hepatic contents of P450IIB2 (to levels of 50-80 pmol/mg of protein) and, to a lesser extent, P450IIB1 (1-5 pmol/mg of protein) in male and female rats. Supplement of T3 to thyroidectomized rats reversed the increased contents to levels similar to those observed in normal rats. Hypophysectomy also increased both P450IIB1 and P450IIB2 protein, and their levels in both sexes were similar to that of P450IIB2 in thyroidectomized rats. Treatment of hypophysectomized rats with T3 as well as human GH suppressed hepatic contents of P450IIB1 and P450IIB2. In a hepatocyte culture including 2 mM phenobarbital, T3 and GH suppressed both P450IIB1 and P450IIB2. Other thyroid hormone derivatives, including thyroxine, D-T3, and reversed T3, also showed suppressive effects, in parallel with the potencies for their stimulatory action that have been reported. These results indicate that thyroid hormone may suppress both P450IIB1 and P450IIB2 by a direct effect on the liver, but not by an indirect effect through the modulation of pituitary GH synthesis. The high susceptibility of hepatic P450IIB2 to thyroid hormone-induced suppression also indicates that constitutive and phenobarbital-induced levels of P450IIB2 are suppressively regulated preferentially by thyroid hormone, in contrast to the high susceptibility to GH of P450IIB1 in rat liver. In addition, a difference in the suppressive mechanisms of thyroid hormone and GH was suggested by the difference in susceptibility to cycloheximide.

Animals↗
PubMed1996

A novel missense mutation in the thyroid hormone receptor beta gene in a kindred with resistance to thyroid hormone.

Direct sequencing of exon 9 of the thyroid hormone receptor beta (TRbeta) gene in a kindred with resistance to thyroid hormone revealed a substitution of threonine for methionine in codon 313 in one allele resulting from a T to C transition. This is a novel missense mutation that resides in one of the two mutational "hot-spot" regions of the TR beta gene suggesting altered triiodothyronine binding to this mutant receptor.

Adult↗
PubMed1996

Post-transcriptional induction of beta 1-adrenergic receptor by retinoic acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone receptors.

Thyroid hormone (triiodothyronine; T3) has been shown to control the expression of beta 1-adrenergic receptors (beta 1-AR) in cardiac myocytes, but not in C6 glioma cells. This cell specificity has been attributed to low expression of T3 receptors and high expression of the c-erbA alpha 2 splice variant that interferes with the action of T3. To check this hypothesis we have expressed the c-erbA/thyroid hormone receptor (TR) alpha 1 gene in C6 glioma cells and investigated their response to thyroid hormone. Cells expressing TR alpha 1, but not wild-type cells, were responsive to T3 as shown by increased expression of mitochrondrial hydroxymethylglutaryl CoA synthase after T3 exposure. However, T3 had no effect on beta 1-AR gene expression in either set of cells. The beta 1-AR mRNA concentrations were, however, altered by retinoic acid (RA) treatment. Retinoic acid caused a rapid up-regulation of beta 1-AR mRNA levels that was blocked by cycloheximide. Retinoic acid did not increase the beta 1-AR gene transcription rate in run-on experiments. These results indicate an indirect post-transcriptional effect of RA. Control of beta 1-AR expression in C6 cells is also exerted at the translational level, because there was no correlation between mRNA and protein induction, as determined by radioligand binding studies. We conclude that lack of responsiveness of the beta 1-AR gene in C6 cells to T3 is not due to high expression of c-erbA alpha 2 but to undefined cell-specific factors.

Animals↗
PubMed1992

A point mutation in the 3,5,3'-triiodothyronine-binding domain of thyroid hormone receptor-beta associated with a family with generalized resistance to thyroid hormone.

A tight linkage between generalized resistance to thyroid hormone (GRTH) and the thyroid hormone receptor-beta (TR beta) gene is indicated. We evaluated a family with GRTH for the TR beta gene. We found that a new point mutation, consisting of a cytosine to adenine replacement at nucleotide position 1642, resulted in substitution in codon 448 in the T3-binding domain of TR beta. This base substitution was found in only one allele of affected members, but not in unaffected members of the family. The in vitro translation products of this mutant TR beta gene demonstrated significantly reduced T3-binding affinity. Previously, others have reported a kindred with GRTH, in that the same codon was subjected to proline to histidine replacement due to a mutation consisting of a cytosine to adenine replacement at nucleotide position 1643. There appeared to be a significant phenotypic difference between our kindred and that described by others.

Alleles↗
PubMed2007

The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions.

The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRDeltabeta3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRDeltabeta3 can be translated from a specific TRDeltabeta3 mRNA or is coexpressed with TRbeta3 from a single transcript that contains an internal TRDeltabeta3 translation start site. In these studies, we provide evidence that the TRbeta3/Deltabeta3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRbeta3 with other TR isoforms and investigated mechanisms of action of TRDeltabeta3 at specific thyroid hormone response elements (TREs) in two cell types. TRbeta3 was the most potent isoform, but TR potency was TRE dependent. TRDeltabeta3 acted as a cell-specific and TRE-dependent modulator of TRbeta3 when coexpressed at low concentrations. At higher concentrations, TRDeltabeta3 was a TRE-selective and cell-specific antagonist of TRalpha1, -beta1, and -beta3. Both TRbeta3 and TRDeltabeta3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRDeltabeta3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T3 action.

Animals↗
PubMed1993

Thyroid hormone receptor dimerization is required for dominant negative inhibition by mutations that cause thyroid hormone resistance.

The syndrome of thyroid hormone resistance (THR) is caused by multiple distinct mutations of the ligand-binding domain of the thyroid hormone beta receptor. Although the mutant receptors are transcriptionally inactive, they inhibit normal receptor function in a dominant negative manner to cause hormone resistance. Because most of the naturally occurring mutations are clustered within two areas that lie on either side of a putative dimerization region, we hypothesized that receptor dimerization was important for dominant negative inhibition. In gel mobility shift assays, two THR mutants (G345R and P453H) formed homodimers as well as heterodimers with the retinoic acid X receptor alpha. In contrast, an artificial mutation (L428R) in one of the hydrophobic heptad repeats of the putative receptor dimerization domain impaired heterodimerization with retoinoic acid X receptor alpha without altering the formation of homodimers. Double mutants containing either of the THR mutations along with the dimerization mutation formed homodimers but not heterodimers, reflecting the properties of the dimerization mutant alone. In transient expression assays using positively (TRETKLuc) or negatively (TSH alpha Luc) regulated reporter genes, the dominant negative activity of the THR mutants was eliminated by the addition of the dimerization mutation. These results support a mechanism for dominant negative activity by THR mutants in which functionally inactive heterodimers bind to DNA to inhibit access by normal receptors.

Amino Acid Sequence↗
PubMed1998

T426I a new mutation in the thyroid hormone receptor beta gene in a sporadic patient with resistance to thyroid hormone and dysmorphism. Mutations in brief no. 192. Online.

Resistance to thyroid hormone (RTH) is a rare inherited autosomal syndrome caused by mutations in the thyroid hormone receptor beta (TRb) gene. Although RTH is generally a familiar disease, 15% of sporadic cases have been also reported. So far, about 80 different mutations of TRb gene have been identified in patients affected by RTH. All these mutations localize to the binding domain and most of them cluster within two "hot spots" (codons 310-349 and codons 429-460). Here we describe in a patient with RTH, a new mutation in codon 426 (T426I) of the TRb gene leading to a threonine to isoleucine substitution. This is a "de nova" mutation which localizes in the so-called "cold" region, outside the two known "hot spots". The patient had the hallmark of RTH: elevated FT3 and FT4, normal TSH, and clinical features of both hypo and hyperthyroidism. Moreover, several dysmorphisms were present including triangular face appearance, synophris, low set ears, micrognathia with malocclusion, large upper incisors and apparent lack of lower cuspids which have not previously described in RTH patients.

Craniofacial Abnormalities↗
PubMed1981

Dependency of maximum goitrogenic response on some minimal level of thyroid hormone production.

Thyroidal activity was studied in chicks given dietary thiouracil in conjunction with daily doses of thyroxine and with diets adequate and deficient in iodine. DL-thyroxine administered at doses up to 1.0 microgram per day for 10 to 12 days had no effect or slightly increased thyroid weight. Both the epithelial and colloid components of the thyroid gland were increased in response to thiouracil and to thiouracil in combination with low dosages of exogenous thyroxine. Radioiodine uptake was increased above the control with thiouracil and with thiouracil in conjunction with .5 and 1.0 microgram DL-thyroxine given daily. Birds receiving thiouracil, with and without exogenous thyroxine, showed a different pattern of radioiodine uptake and release than the control birds. Thiouracil-treated birds showed a rapid uptake of iodine following its administration, which was followed by a rapid decline immediately after peak accumulation, whereas in control birds thyroidal radioiodine concentration reached a plateau at the maximum concentration attained. The goitrogenic response to thiouracil was much greater when the diet was supplemented with iodine than when the diet was iodine-deficient. Thyroids under iodine deficiency contained greater percentages of epithelial tissue than with iodine-supplemented diets. Thyroid glands of chicks given thiouracil in an iodine-supplemented diet contained much more colloid than glands from iodine-deficient chicks with or without thiouracil. DL-thyroxine at a dosage of .5 microgram per day to chicks given thiouracil in an iodine-adequate diet increased, whereas higher dosages decreased thyroidal colloid. It is concluded that some minimal concentration of thyroid hormone is required for maximum goitrogenic response. It is not clear whether the response is entirely due to an effect on thyrotropin production or whether there is an effect of thyroid hormone on the thyroid gland itself.

Animal Feed↗
PubMed2002

RXR acts as a coregulator in the regulation of genes of the hypothalamo-pituitary axis by thyroid hormone receptors.

Thyroid hormone receptors (TRs) often modulate transcriptional activity of target genes by heterodimerization with the 9-cis retinoic acid receptor (RXR). On positive thyroid response elements (TREs), RXR favors binding of the TR-RXR complex to DNA and stimulates transcription. RXR action on negative TREs is unclear. Furthermore, the single half-site configuration of many negative TREs does not favor the binding of a classic TR-RXR heterodimer. In a comparative study using CV-1 cells (relatively RXR- and TR-deficient) and JEG-3 cells (relatively TR-deficient), we demonstrate the importance of RXR in the negative transcriptional regulation of genes of the hypothalamo-pituitary axis by tri-iodothyronine. While RXR has variable effects on ligand-independent activation produced by TRs, it was required for efficient ligand-dependent repression of the TRH gene for TRalpha1 and TRbeta1 and of the TSH genes by all TRs. Using different RXR constructs we also observed the importance of the C-terminus of RXR but not of the N-terminus nor the DNA-binding domain, in the potentiation of negative regulation. We thus suggest that, with regard to negative regulation of the TRH and TSH genes by thyroid hormones, RXR behaves more like a cofactor than a classic heterodimerization partner.

Animals↗