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)

Cytosolic proteins may play an important role in the intracellular transport of bile acids in enterocytes. The lithocholate binding properties of cytosolic protein from bovine small intestine were studied. Lithocholate binding was observed in the Y (45-50 kDa), Y' (30-35 kDa), and Z fractions (10-15 kDa) following gel filtration of cytosol. A Y protein with glutathione S-transferase activity (46 kDa) was purified by S-octyl-glutathione affinity chromatography and chromatofocusing (eluted at pH 7.5) of the Y fraction. Two Y' bile acid binding proteins with dihydrodiol dehydrogenase activity were partially purified from the Y' fraction by chromatofocusing and hydroxyapatite-HPLC. The lithocholate binding affinity of Y' protein (Kd < 0.35 microM) was higher than that of Y protein (Kd = 2 microM) and was comparable to that of Z protein (Kd = 0.2 microM). The binding affinity of Y protein was higher for bilirubin (Kd = 2.5 microM) than that for BSP (Kd = 200 microM). This was comparable to the binding affinity of bovine hepatic Y protein. These data indicate that Y' and Z proteins participate in the intracellular transport of bile acids from the brush border to the basolateral pole in enterocytes.
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PMID:Lithocholate binding by Y and Y' proteins in bovine small intestine. 132 60

Some reports link human hepatic porphyria with a risk of hepatocellular carcinoma. Hepatic protoporphyria and uroporphyria were induced in mice by feeding griseofulvin and hexachlorobenzene (HCB), respectively. These chemicals also cause liver cancer. Hepatic immunoreactive cytosolic levels of heme-binding Z protein (HBP) were reduced by 81% (griseofulvin) and 55% (HCB). In contrast, both treatments caused a greater than 4-fold increase in the immunoreactive levels of glutathione S-transferase isozymes (GST) which like HBP also bind heme. Unlike in vitro studies in the presence of porphyrins, no cross-linking of HBP was observed in vivo.
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PMID:Modulation of hepatic heme-binding Z protein in mice by the porphyrogenic carcinogens griseofulvin and hexachlorobenzene. 273 Nov 54

Hepatocyte nodules and hepatocellular carcinomas were induced in male Fischer rats using the resistant hepatocyte model. The immunoreactive cytosolic levels of the heme-binding Z protein (HBP) were reduced by 56% (P less than 0.001; 2-tailed t-test) in early hepatocyte nodules (25 weeks) and hepatocellular carcinomas (10-12 months). This finding is in accordance with the previously reported reduced heme content of hepatocyte nodules and is consistent with the postulated role for HBP in intracellular heme transport and distribution. The immunoreactive levels of the glutathione S-transferase isozymes (GST) which like HBP bind heme, were elevated 2-fold (P less than 0.01) in early and late hepatocyte nodules and were unchanged in hepatocellular carcinomas.
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PMID:Decreased cytosolic levels of the heme binding Z protein in rat hepatocyte nodules and hepatocellular carcinomas. 320 30

1. The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol-induced acute renal failure (ARF). 2. The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced. 3. The initial (0-10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5-10 min in control rats and 10-15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min. 4. The plasma-protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites. 5. The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S-transferase (GST) activity and a 36% reduction in the GST activity of ligandin. 6. The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.
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PMID:Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure. 322 67

The Epstein-Barr virus (EBV) BZLF1 (Z) immediate-early transactivator initiates the switch between latent and productive infection in B cells. The Z protein, which has homology to the basic leucine zipper protein c-Fos, transactivates the promoters of several replicative cycle proteins. Transactivation efficiency of the EBV BMRF1 promoter by Z is cell type dependent. In B cells, in which EBV typically exists in a latent form, Z activates the BMRF1 promoter inefficiently. We have discovered that the p65 component of the cellular factor NF-kappa B inhibits transactivation of several EBV promoters by Z. Furthermore, the inhibitor of NF-kappa B, I kappa B alpha, can augment Z-induced transactivation in the B-cell line Raji. Using glutathione S-transferase fusion proteins and coimmunoprecipitation studies, we demonstrate a direct interaction between Z and p65. This physical interaction, which requires the dimerization domain of Z and the Rel homology domain of p65, can be demonstrated both in vitro and in vivo. Inhibition of Z transactivation function by NF-kappa B p65, or possibly by other Rel family proteins, may contribute to the inefficiency of Z transactivator function in B cells and may be a mechanism of maintaining B-cell-specific viral latency.
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PMID:The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF-kappa B. 811 25

We have cloned and characterised a cDNA encoding Z protein of recently identified MX strain of lymphocytic choriomeningitis virus (LCMV) persistently infecting human MaTu cells. Deduced amino acid sequence of LCMV MX Z protein showed 88.9% identity with that of the LCMV Armstrong (ARM) strain and 80.9% identity with that of the LCMV Traub (TRA) strain. It contained conserved zinc-binding RING finger domain and C-terminal proline-rich region. Northern blot analysis of total RNA from MaTu cells revealed presence of abundant truncated forms of L RNA. Z protein-specific rabbit antibodies were produced to glutathione S-transferase (GST)-Z fusion protein expressed in E. coli and used for the detection of Z protein in MaTu cells. Western blot and immunofluorescence analyses detected relatively high levels of Z protein indicating its role in maintenance of persistent LCMV.
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PMID:Sequence and characterisation of the Z gene encoding ring finger protein of the lymphocytic choriomeningitis virus MX strain. 1035 42

Here, we describe a proteomics approach to study protein expression changes in differentiating Caco-2 cells. Caco-2 is a colorectal carcinoma cell line, which upon differentiation loses its tumorigenic phenotype and displays characteristics of mature enterocytes, including brush borders with microvilli. Cells were grown in culture flasks and harvested at different stages of differentiation (days post-confluence: -3, 0, 3, 7, 10, 14, and 18). Two-dimensional gel electrophoresis was used to analyse proteome changes. Approximately 1400 protein spots were detected within the Caco-2 proteome, within the pH 4-7 range. Two-dimensional gel electrophoresis allowed for the detection of 18 proteins from which the levels of expression were found to be associated with differentiation. Of these proteins, 11 were identified by means of MALDI-TOF or NANO-ESI-MS/MS mass spectrometry and include liver fatty acid binding protein (FABL), three forms of alpha-enolase (ENOA), nucleoside diphosphate kinase A (NDKA), cofilin-1 (COF1), translationally controlled tumour protein (TCTP), mitochondrial 60-kDa heat shock protein (CH60), probable protein disulfide isomerase (ER60), creatine kinase B (KCRB), and glutathione S-transferase alpha (GTA1). Thus, proteomics revealed that the differentiation-related change in phenotype of Caco-2 involves changes in a variety of distinct biochemical pathways. Some of these proteins have not been shown before to be associated with Caco-2 differentiation (ER60; COF1; CH60; NDKA; TCTP and ENOA). Therefore, processes related to protein folding and disulfide bridge formation, cytoskeleton formation and maintenance, nucleotide metabolism, glycolysis as well as tumorigenesis-associated proteins may be involved in Caco-2 differentiation. Changes in the expression of CH60, TCTP, GTA1, NDKA, and FABL have also been reported to be associated with in vivo colon carcinogenesis. These findings illustrate that a combination of proteomics and cell culture is a useful approach to find markers for Caco-2 differentiation, which could contribute to the comprehension of the process of colon carcinogenesis.
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PMID:Proteome analysis reveals novel proteins associated with proliferation and differentiation of the colorectal cancer cell line Caco-2. 1292 71

Although the physiological roles of the individual bile acid synthetic enzymes have been extensively examined, relatively little is known regarding the function of intracellular bile acid-binding proteins. Male L-FABP (liver fatty-acid-binding protein) gene-ablated mice were used to determine a role for L-FABP, the major liver bile acid-binding protein, in bile acid and biliary cholesterol metabolism. First, in control-fed mice L-FABP gene ablation alone increased the total bile acid pool size by 1.5-fold, especially in gall-bladder and liver, but without altering the proportions of bile acid, cholesterol and phospholipid. Loss of liver L-FABP was more than compensated by up-regulation of: other liver cytosolic bile acid-binding proteins [GST (glutathione S-transferase), 3alpha-HSD (3alpha-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7alpha-hydroxylase) and CYP27A1 (sterol 27alpha-hydroxylase)], membrane bile acid translocases [canalicular BSEP (bile salt export pump), canalicular MRP2 (multidrug resistance associated protein 2), and basolateral/serosal OATP-1 (organic anion transporting polypeptide 1)], and positive alterations in nuclear receptors [more LXRalpha (liver X receptor alpha) and less SHP (short heterodimer partner)]. Secondly, L-FABP gene ablation reversed the cholesterol-responsiveness of bile acid metabolic parameters such that total bile acid pool size, especially in gall-bladder and liver, was reduced 4-fold, while the mass of biliary cholesterol increased 1.9-fold. The dramatically reduced bile acid levels in cholesterol-fed male L-FABP (-/-) mice were associated with reduced expression of: (i) liver cytosolic bile acid-binding proteins (L-FABP, GST and 3alpha-HSD), (ii) hepatic bile acid synthetic enzymes [CYP7A1, CYP27A1 and SCP-x (sterol carrier protein-x/3-ketoacyl-CoA thiolase)] concomitant with decreased positive nuclear receptor alterations (i.e. less LXRalpha and more SHP), and (iii) membrane bile acid transporters (BSEP, MRP2 and OATP-1). These are the first results suggesting a physiological role for the major cytosolic bile acid-binding protein (L-FABP) in influencing liver bile metabolic phenotype and gall-bladder bile lipids of male mice, especially in response to dietary cholesterol.
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PMID:Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice. 1598 32

To identify biomarkers associated with the development of hepatocellular carcinoma (HCC) in CuZn superoxide dismutase (CuZnSOD, Sod1) deficient mice, 2-DE followed by MS analysis was carried out with liver samples obtained from 18-month-old Sod1-/- and +/+ mice. The intracellular Ca binding protein, regucalcin (RGN), showed a divergent alteration in Sod1-/- samples. Whereas elevated RGN levels were observed in -/- samples with no obvious neoplastic changes, marked reduction in RGN was observed in -/- samples with fully developed HCC. GST mu1 (GSTM1), on the other hand, showed a significant increase only in the neoplastic regions obtained from Sod1-/- livers. No change in GSTM1 was observed in the surrounding normal tissues. Marked reduction was observed in two intracellular lipid transporters, fatty acid binding protein 1 (FABP1) and major urinary protein 11 and 8 (MUP 11&8), in Sod1-/- samples. Analysis of additional samples at 18-22 months of age showed a three-fold increase in enolase activities in Sod1-/- livers. Consistent with previous findings, carbonic anhydrase 3 (CAIII) levels were significantly reduced in Sod1-/- samples, and immunohistochemical analysis revealed that the reduction was not homogenous throughout the lobular structure in the liver.
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PMID:Identification of biomarkers associated with the development of hepatocellular carcinoma in CuZn superoxide dismutase deficient mice. 1751 84

Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.
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PMID:Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives. 3208 63


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