Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats were fed selenium-deficient (less than 0.005 mg selenium/kg) or selenium-supplemented diets (0.1 mg selenium/kg, as Na2SeO2) for up to five wks from weaning to assess the effects of developing selenium deficiency on the metabolism of thyroid hormones. Within two wks 3:5,3'-triiodothyronine (T3) production from thyroxine (T4) in liver homogenates from selenium-deficient rats was significantly lower compared with the activity in liver homogenates from selenium-supplemented rats. This decreased activity was probably responsible, in part, for the higher T4 and lower T3 concentrations in plasma from the selenium-deficient rats after 3, 4, and 5 weeks of experiment. Repletion of selenium-deficient rats with single intra-peritoneal injections of 200 micrograms selenium/kg body wt. (as Na2SeO3) 5 days before sampling reversed the effects of the deficiency on thyroid hormone metabolism and significantly increased liver and plasma glutathione peroxidase activities. However a dose of 10 micrograms selenium/kg body wt given to rats of similar low selenium status had no effect on thyroid hormone metabolism or glutathione peroxidase activity but did reverse the increase in hepatic glutathione S-transferase activity characteristic of severe selenium deficiency. Imbalances in thyroid hormone metabolism are an early consequence of selenium deficiency and are probably not related to changes in hepatic xenobiotic metabolizing enzymes associated with severe deficiency.
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PMID:The effects of selenium depletion and repletion on the metabolism of thyroid hormones in the rat. 238 Jul 4

A specific radioimmunoassay (RIA) has been developed that has sufficient sensitivity to allow measurement of the changes in plasma and tissue glutathione S-transferase (GST) YaYa concentrations which occur following thyroid hormone administration in the rat. Using the RIA it was demonstrated that the only tissues that had significant amounts of GST YaYa were liver, small gut and kidney. Administration of triiodothyronine (T3) or thyroxine (T4) resulted in increases in plasma GST YaYa concentration and in animals given high doses of T4 plasma alanine aminotransferase activity was also elevated. Thyroid hormone administration produced a significant fall in the hepatic content of GST YaYa and in total GST activity, as assessed using 1-chloro-2,4-dinitrobenzene as substrate. It is concluded that the elevated plasma GST YaYa concentrations observed following administration of thyroid hormones result from hepatic damage, not from induction of hepatic synthesis of the enzyme.
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PMID:Hepatic damage in the rat following administration of thyroxine or triiodothyronine, assessed by measurement of plasma glutathione S-transferase YaYa concentrations. 381 55

Goitrin is a potent goitrogen that has been shown to induce glutathione S-transferase (GST) activity and to increase aflatoxin detoxification. In the present study with rats, dietary goitrin (200 mg/kg diet) produced a hypothyroid state and significantly increased levels of hepatic GSSG (1.4-fold), GST protein (1.4-fold) and GST activity against chlorodinitrobenzene (CDNB) (1.7-fold). Cotreatment with dietary triiodothyronine (T3) reversed these effects in a dose-related manner. Intestinal GST activities against CDNB and epoxynitrophenoxypropane did not change with goitrin or T3 treatment. HPLC analysis showed that, in the liver, goitrin treatment increased the levels of GST-1b and -7 by 3.5- and 5-fold, respectively, and decreased the level of GST-3 by 50%. Cotreatment with T3 returned levels of GST-7 and -3 to control levels but only partially reduced the level of GST-1b. In the small intestine, goitrin increased the level of GST-1b by 28% and decreased the level of GST-7 by 34% compared with those of controls; thyroid hormone treatment produced no additional effect on GST in this organ. Selenium deficiency altered thyroid hormone status but significantly affected the level only of hepatic GST-3, which was reduced by 30% compared with that of controls. These results indicate that a modified thyroid hormonal status plays an important role in the GST-inducing effects of goitrin. A possible mechanism of thyroid-dependent GST induction by goitrin is discussed.
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PMID:Modulation of glutathione S-transferase activity and isozyme pattern in liver and small intestine of rats fed goitrin- and T3-supplemented diets. 753 9

Thyroid hormone (T3) stimulates gene transcription by activation of thyroid hormone receptors (TRs), which bind to thyroid hormone response elements in T3-regulated genes. Retinoid-X receptors (RXRs), major members of the TR auxiliary proteins, have recently been shown to form TR-RXR heterodimers, to enhance the binding of the TRs to thyroid hormone response elements, and to augment TR-mediated transcriptional activation. In this report, we provide evidence that a putative adaptor(s), other than RXR, may be involved in T3-stimulated gene transcription. First, T3-stimulated, but not basal, transcription from the rat GH promoter was progressively and specifically inhibited by the addition of increasing amounts of either GST-TR beta or GST-RXR beta in a cell-free in vitro transcription. Second, this specific transcriptional inhibition is not due to disruption of the DNA-binding activity of the endogenous TR-RXR complex. These results suggest that inhibition of T3-stimulated transcription may be due to the sequestration of a limiting adaptor molecule(s). Hence, we hypothesize that a limiting adaptor(s), which may act as a bridging molecule between the TR-RXR complex and the basal transcriptional machinery, may be sequestered by either GST-TR beta or GST-RXR beta, resulting in the inhibition of T3-stimulated transcription.
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PMID:A potential transcriptional adaptor(s) may be required in thyroid hormone-stimulated gene transcription in vitro. 775 May 3

Liver-type L-arginase is a major urea-cycle enzyme which is strongly induced during amphibian metamorphosis, but little is known about the molecular mechanisms underlying this induction. As a first step towards elucidating the possible mechanisms, we have isolated a cDNA clone for L-arginase from an adult Xenopus laevis liver cDNA library. Sequence comparison of Xenopus liver-type L-arginase cDNA shows a strong conservation at the amino acid level with those of human, rat and yeast. Using a Xenopus arginase cDNA fragment as a hybridization probe, we have shown by Northern blotting that the gene is highly expressed in the liver, and very slightly in kidney and spleen, of adult Xenopus. The expression is developmentally regulated. Only traces of arginase mRNA can be detected in pre-metamorphic tadpoles, but its accumulation increases very markedly at the onset of natural metamorphosis, being maintained at a high concentration constitutively upon completion of this developmental process. Amphibian metamorphosis is under the strict control of thyroid hormones. It is therefore significant that exposure of pre-metamorphic tadpoles (at stages before endogenous thyroid hormone secretion) to exogenous hormone (1 nM triiodothyronine) precociously activated the L-arginase gene. The time course of this precocious hormonal induction paralleled that of serum albumin gene in the liver. Polyclonal antibodies were raised against recombinant Xenopus L-arginase expressed in Escherichia coli as a fusion protein with glutathione S-transferase in the plasmid expression vector pGEX. Western blotting using this antibody showed that, although arginase mRNA is present in high concentration in Xenopus tadpole liver at the onset of natural metamorphosis, the protein is detected only upon its completion. Our results show a complex transcriptional and post-transcriptional regulation of the Xenopus liver-type L-arginase gene during post-embryonic development. They also demonstrate that this gene can be exploited as a target for thyroid hormones in further studies to analyze the mechanisms underlying the establishment of the adult phenotype during amphibian metamorphosis.
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PMID:Developmental and hormonal regulation of the Xenopus liver-type arginase gene. 791 84

Rat Rev-erbA alpha (rRev), which is related to thyroid hormone receptor (TR), is a conserved member of the nuclear hormone receptor superfamily whose physiological roles are unknown ("orphan" receptor). We studied DNA binding of rRev in vitro by electrophoretic mobility shift assay. A fusion protein was constructed, called NGR.Rev, containing part of the N terminus of the glucocorticoid receptor fused to nearly full-length rRev. Inasmuch as rRev and TR share homology in their DNA-binding domains, we tested binding to three different thyroid hormone response elements (TREs) in which the half-sites are arranged in different orientations. NGR.Rev bound direct repeats (DR4), but not palindromic (TREpal) or inverted palindromic (F2H) repeats. Also, transfection of CV1 cells with a reporter gene containing the luciferase gene under control of the inducible thymidine kinase promoter resulted in an increase in luciferase activity when NGR.Rev was cotransfected and when the thymidine kinase promoter contained DR4. In addition, a series of deletions in the ligand-binding domain of NGR.Rev revealed regions that can modulate DNA binding. Finally, we studied DNA binding of bacterially produced fusion proteins that contain the DNA-binding domains of rRev or rTR alpha fused to glutathione S-transferase, to a panel of natural TREs. Our results indicate that Rev binds DNA with a different specificity than TR alpha-1 and might be involved in the regulation of a subset of thyroid hormone-regulated genes.
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PMID:Rat Rev-erbA alpha, an orphan receptor related to thyroid hormone receptor, binds to specific thyroid hormone response elements. 801 47

Unliganded thyroid hormone receptor (TR) functions as a transcriptional repressor of genes bearing thyroid hormone response elements in their promoters. Binding of hormonal ligand to the receptor releases the transcriptional silencing and leads to gene activation. Previous studies showed that the silencing activity of TR is located within the C-terminal ligand-binding domain (LBD) of the receptor. To dissect the role of the LBD in receptor-mediated silencing, we used a cell-free transcription system containing HeLa nuclear extracts in which exogenously added unliganded TRbeta repressed the basal level of RNA polymerase II-driven transcription from a thyroid hormone response element-linked template. We designed competition experiments with a peptide fragment containing the entire LBD (positions 145 to 456) of TRbeta. This peptide, which lacks the DNA-binding domain, did not affect basal RNA synthesis from the thyroid hormone response element-linked promoter when added to a cell-free transcription reaction mixture. However, the addition of the LBD peptide to a reaction mixture containing TRbeta led to a complete reversal of receptor-mediated transcriptional silencing in the absence of thyroid hormone. An LBD peptide harboring point mutations, which severely impair receptor dimerization, also inhibited efficiently the silencing activity of TR, indicating that the relief of repression by the LBD was not due to the sequestration of TR or its heterodimeric partner retinoid X receptor into inactive homo- or heterodimers. We postulate that the LBD peptide competed with TR for a regulatory molecule, termed a corepressor, that exists in the HeLa nuclear extracts and is essential for efficient receptor-mediated gene repression. We have identified the region from positions 145 to 260 (the D domain) of the LBD as a potential binding site of the putative corepressor. We observed further that a peptide containing the LBD of retinoic acid receptor (RAR) competed for TR-mediated silencing, suggesting that the RAR LBD may bind to the same corepressor activity as the TR LBD. Interestingly, the RAR LBD complexed with its cognate ligand, all-trans retinoic acid, failed to compete for transcriptional silencing by TRbeta, indicating that the association of the LBD with the corepressor is ligand dependent. Finally, we provide strong biochemical evidence supporting the existence of the corepressor activity in the HeLa nuclear extracts. Our studies demonstrated that the silencing activity of TR was greatly reduced in the nuclear extracts preincubated with immobilized, hormone-free glutathione S-transferase-LBD fusion proteins, indicating that the corepressor activity was depleted from these extracts through protein-protein interactions with the LBD. Similar treatment with immobilized, hormone-bound glutathione S-transferase-LBD, on the other hand, failed to deplete the corepressor activity from the nuclear extracts, indicating that ligand binding to the LBD disrupts its interaction with the corepressor. From these results, we propose that a corepressor binds to the LBD of unliganded TR and critically influences the interaction of the receptor with the basal transcription machinery to promote silencing. Ligand binding to TR results in the release of the corepressor from the LBD and triggers the reversal of silencing by allowing the events leading to gene activation to proceed.
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PMID:Transcriptional silencing by unliganded thyroid hormone receptor beta requires a soluble corepressor that interacts with the ligand-binding domain of the receptor. 862 57

The influence of dietary fibre on the biological effects of glucosinolates was investigated in gnotobiotic rats harbouring a human whole faecal flora. Animals were fed for 6 wk with diets containing 12% rapeseed meal (RSM) supplemented or not supplemented with 10% inulin (INL) or oat fibre. Both fibre types enhanced the liver hypertrophy due to RSM to equal extents, but had different effects on the other glucosinolate-related toxic effects. INL partially restored a normal thyroid hormone status whereas kidney weight, goitre and growth deficit were increased on exposure to the diet containing oat fibre. Oat fibre and, to a lesser extent, INL modulated the alterations of digestive xenobiotic-metabolizing enzymes (XME) induced by RSM. They counter-balanced the induction of hepatic cytochrome P-450 and lessened the induction of uridine diphosphate-glucuronosyltransferase in the liver but did not modify depletion of its activity in the small intestine. On the other hand, they enhanced the induction of glutathione S-transferase in the liver and the large intestine but not in the small intestine. These findings give new evidence that the biological effects of naturally occurring non-nutrient compounds are closely dependent on the composition of the diet. Two mechanisms are proposed to explain the different influence of INL and oat fibre on RSM toxicity. Their different fermentative characteristics could lead to a modulation of the bacterial metabolism of glucosinolates in the caecum. Alternatively, their own action on the digestive XME could modify the subsequent metabolism of bacterial glucosinolate derivatives.
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PMID:Modulation of the biological effects of glucosinolates by inulin and oat fibre in gnotobiotic rats inoculated with a human whole faecal flora. 888 67

The thyroid hormone receptors (TR) bind to cis-acting DNA elements as heterodimers with the retinoid X receptors (RXR). These heterodimers display distinct specificities in mediating the hormonal response to target gene transcription. We characterized the interaction between TRalpha1 and RXRalpha via their ligand binding domains (LBDs) and the effect of ligands on the interaction using a yeast two-hybrid system. The DNA binding domain (BD) of yeast Gal4 fusion to the LBD of TRalpha1 had no transcriptional activity on its own, but when it was coexpressed with the activation domain (AD) of yeast Gal4 fusion to LBD of RXRalpha conferred activation to a reporter gene harboring a Gal4 binding site, indicating that LBDs of TRalpha1 and RXRalpha interact with each other in solution. Furthermore, T3 and 9-cis-RA increased the reporter activity, and an additive effect was observed when both ligands were added, indicating that the TRalpha1.RXRalpha heterodimerization is augmented by their respective ligands in vivo. Using an in vitro pull-down experiment, we confirmed the ligand-dependent interaction observed in the yeast system. Matrix-bound glutathione S-transferase-RXRalpha specifically coprecipitated the 35S-labeled TRalpha1 above the control, and associated 35S-labeled TRalpha1 was increased by the addition of T3 and 9-cis-RA. These results imply a complex, sensitive cross-talk in vivo among nuclear receptors and their respective ligands through distinct hormonal signaling pathways.
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PMID:Ligand-dependent heterodimerization of thyroid hormone receptor and retinoid X receptor. 929 26

The kidney and several other thyroid hormone-responsive tissues contain a NADP-regulated thyroid hormone (TH)-binding protein (THBP), with an apparent molecular mass of 36 kDa on SDS-PAGE, responsible for most of the intracellular high-affinity T3 and T4 binding. THBP was purified to homogeneity from human kidney cytosol and used to generate proteolytic peptides. Microsequencing of four peptides revealed identity to amino acid sequences deduced from a human cDNA homolog to a cDNA encoding kangaroo mu-crystallin. This protein is a major structural kangaroo lens protein with no known function in other species. A full-sized cDNA (TH5.9) was isolated by 5'- and 3'-rapid amplification of cDNA ends using a human brain cDNA library and gene-specific PCR primers, confirming identity to the previously cloned human cDNA. The TH5.9 cDNA encodes a 314-residue protein (theoretical mol wt = 33,775) with significant homologies (40 to 60%) with two bacterial enzymes: lysine cyclodeaminase and ornithine cyclodeaminase. The TH5.9 cDNA was expressed in Escherichia coli as a glutathione S-transferase (GST) fusion protein. Purified GST fusion protein, but not GST, bound T3 specifically with high affinity [dissociation constant (Kd) = 0.5 nM] in the presence of NADPH, and was labeled by UV-driven cross-linking of underivatized [(125)I]T3. T3 binding and photoaffinity labeling of GST fusion protein were activated by NADPH [activation constant (K[act]) = 10(-8) M], but not by NADH. The expressed protein displays the appropriate binding properties, indicating that TH5.9 cDNA encodes the NADP-regulated THBP characterized in human tissues.
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PMID:Purification, molecular cloning, and functional expression of the human nicodinamide-adenine dinucleotide phosphate-regulated thyroid hormone-binding protein. 932 54


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