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)

Live vaccine vectors are usually very effective and generally elicit immune responses of higher magnitude and longer duration than nonliving vectors. Consequently, much attention has been turned to the engineering of oral pathogens for the delivery of foreign antigens to the gut-associated lymphoid tissues. However, no bacterial vector has yet been designed to specifically take advantage of the nasal route of mucosal vaccination. Herein we describe a genetic system for the expression of heterologous antigens fused to the filamentous hemagglutinin (FHA) in Bordetella pertussis. The Schistosoma mansoni glutathione S-transferase (Sm28GST) fused to FHA was detected at the cell surface and in the culture supernatants of recombinant B. pertussis. The mouse colonization capacity and autoagglutination of the recombinant microorganism were indistinguishable from those of the wild-type strain. In addition, and in contrast to the wild-type strain, a single intranasal administration of the recombinant strain induced both IgA and IgG antibodies against Sm28GST and against FHA in the bronchoalveolar lavage fluids. No anti-Sm28GST antibodies were detected in the serum, strongly suggesting that the observed immune response was of mucosal origin. This demonstrates, to our knowledge, for the first time that recombinant respiratory pathogens can induce mucosal immune responses against heterologous antigens, and this may constitute a first step toward the development of combined live vaccines administrable via the respiratory route.
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PMID:Induction of mucosal immune responses against a heterologous antigen fused to filamentous hemagglutinin after intranasal immunization with recombinant Bordetella pertussis. 875 82

A variety of experimental models have shown that immunization using the glutathione S-transferase from Schistosoma mansoni (Sm28GST) can induce protective immunity against this parasite. This immunity has been related to the production of Th2 type antibodies against the antigen in both mice and humans. The work presented in this paper describes the development of a mucosal immunization protocol using liposomes which is designed to promote production of specific antibodies of isotypes related to a Th2 immune response. The liposomes were multilamellar and composed of various synthetic phospholipid mixtures. The liposome vector was used to convey the Sm28GST antigen to gut associated lymphoid tissue. The association of the Sm28GST antigen with liposomes containing different lipid mixtures was initially studied. The degree of interaction of the antigen was found to increase with the hydrocarbon chain length of the lipids used. It was demonstrated that the protein was present on both the inner and the outer membranes of the liposome vesicles. It was also shown that the major epitopes of Sm28GST were accessible to specific antibodies, confirming a conservation of its main antigenic features. Additionally, enzymatic activity of the protein/liposome complex was also demonstrated, indicating a conservation of the tertiary structure of the protein. An optimal Sm28GST/ liposome complex was established and administered orally to mice. This treatment resulted in both a mucosal and systemic immune response to the antigen Sm28GST. This was demonstrated by the detection of specific IgA in gut washes and specific IgG1, IgG2b in sera. Immunization by Sm28GST/liposome complex followed by challenge with parasite showed that Sm28GST given orally in these conditions bore protective activity. This last result opens the possibility of mucosal vaccination against schistosomiasis.
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PMID:Mucosal vaccination against schistosomiasis using liposome-associated Sm 28 kDa glutathione S-transferase. 891 Oct 8

One of the current goals in vaccine development is the noninvasive administration of protective antigens via mucosal surfaces. In this context, the gut-associated lymphoid tissues have already been extensively explored. Vaccination via the nasal route has only recently been the focus of intensive investigation, and no live vector specifically designed for the respiratory mucosa is yet available. In this study we show that intranasal administration of the recombinant Bordetella pertussis BPGR60, producing the Schistosoma mansoni 28-kDa glutathione S-transferase (Sm28GST) protective antigen fused to filamentous hemagglutinin, induces priming in mice for the production of serum antibodies. In addition to significant levels of anti-Sm28GST immunoglobulin A (IgA) antibodies, high levels of anti-Sm28GST serum antibodies were obtained after intranasal boost with the purified antigen or infection with S. mansoni following intranasal priming with BPGR60. These antibodies were of the IgG1, IgG2a, and IgG2b isotypes, suggesting a mixed immune response. No priming was observed in animals that had received nonrecombinant B. pertussis or purified Sm28GST, indicating specific priming by BPGR60. This priming was also evident in immune protection against S. mansoni challenge. Significant protection against worm burden and egg output was obtained in mice primed with BPGR60 and intranasally boosted with purified Sm28GST. A lower but still significant degree of protection against egg output was also obtained in mice infected with a single dose of BPGR60. These results indicate that intranasal administration of recombinant B. pertussis can prime for serum antibody responses against a foreign antigen and for heterologous protection.
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PMID:Intranasal priming with recombinant Bordetella pertussis for the induction of a systemic immune response against a heterologous antigen. 900 11

Antioxidant enzymes from S. mansoni, cytosolic Cu-Zn superoxide dismutase (CT-SOD), signal-peptide-containing SOD (SP-SOD), glutathione peroxidase (GPX), and glutathione transferase (GST) were compared for their relative levels of transcript expression throughout development in a semiquantitative reverse transcriptase-polymerase chain reaction assay. All of the antioxidant enzymes exhibited a similar pattern of developmental regulation. Adult worms have the highest level of specific mRNA compared with larval stages. GST shows the highest level of expression, being approximately 10-fold more abundant than CT-SOD and SP-SOD and 100-fold more abundant than GPX. This order of expression was nearly consistent for all the developmental stages studied. To localize the antioxidant enzymes, immunofluorescence staining was performed on 3-hr schistosomula and adult worms. GPX, SP-SOD, and CT-SOD were all found to be associated with the adult tegument and gut epithelium. SP-SOD was also associated with organelle and cell membranes of parenchymal cells and interestingly with the spines of adult worms. Schistosomula, on the other hand, showed little immunofluorescence. These studies further demonstrate the developmental regulation of antioxidant enzymes and localize them to the host-parasite interface, supporting the notion that they have a role in allowing adult worms to evade immune attack.
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PMID:Schistosoma mansoni: the developmental regulation and immunolocalization of antioxidant enzymes. 914 42

The effect of propofol on the hepatic and extrahepatic conjugation enzyme systems was assessed in vitro using microsomal and cytosolic preparations of human liver, hamster kidney, lung and gut. The functional activities of phase-II enzymes, including uridine diphosphate-glucuronosyltransferase (UDPGT), glutathione S-transferase (GST) and N-acetyltransferase (NAT) were evaluated in the presence of various concentrations of propofol (0.05-1.0 mmol litre-1), using 1-naphthol, 1-chloro-2,4-dinitrobenzene and p-aminobenzoic acid as substrates respectively. Propofol produced concentration-dependent inhibition of UDPGT activity in human liver microsomes. Propofol did not produce significant inhibition of human hepatic GST activity at concentrations below 1.0 mmol litre-1. In contrast, NAT activity was unaffected by propofol 0.05-1.0 mmol litre-1 in human liver cytosolic preparations. In extrahepatic tissues, hamster renal and intestinal UDPGT activities were significantly inhibited by propofol at 0.25-1.0 mmol litre-1. In these tissues, GST and NAT were unaffected by propofol at 1.0 mmol litre-1. Propofol produced differential inhibition of human liver and hamster extrahepatic conjugation enzymes as a result of different substrate and tissue specificities. The potential interference of the metabolic profile of phase-II enzymes as a result of inhibition by propofol (especially of UDPGT and GST) should be considered when using propofol with other drugs for anaesthesia.
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PMID:Effects of propofol on functional activities of hepatic and extrahepatic conjugation enzyme systems. 1089 55

New Bedford Harbor (NBH), MA, is a federal Superfund site that is heavily contaminated with polychlorinated biphenyls (PCBs) and other halogenated aromatic hydrocarbons (HAHs), including some potent aryl hydrocarbon receptor (AhR) agonists. A population of Atlantic killifish (Fundulus heteroclitus) continues to inhabit this site, despite accumulating extraordinarily high concentrations of PCBs (272 microg/g dry weight). To determine if NBH killifish have developed resistance to HAHs that act through the AhR, we examined the inducibility of cytochrome P4501A1 (CYP1A1), UDP glucuronosyl transferase (UGT), and glutathione S-transferase (GST) in fish from NBH and a reference site, Scorton Creek (SC, Cape Cod, MA; PCB concentrations 0.177 microg/g dry weight). 2,3,7,8-Tetrachlorodibenzofuran (TCDF) induced CYP1A1 mRNA, protein, and activity in SC fish in all tissues examined (liver, heart, gut, gill, kidney, spleen, and gonad). In contrast, NBH fish expressed low levels of CYP1A1 and showed no induction of CYP1A1 mRNA, protein, or activity by TCDF, or induction that was lower in magnitude or required higher doses of inducer. p-Nitrophenol UGT activity was not induced by TCDF in either population, while GST activity with 1-chloro-2,4-dinitrobenzene as substrate was induced only in NBH fish in one experiment. Inducibility of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or beta-naphthoflavone (BNF) was measured in primary hepatocyte cultures prepared from SC and NBH fish. TCDD induced CYP1A1 activity (ethoxyresorufin O-deethylase) to the same degree in hepatocytes from both populations, demonstrating the functionality of the AhR signaling pathway in NBH fish. However, hepatocytes from NBH fish were 14-fold less sensitive to TCDD than were those from SC fish. The nonhalogenated AhR agonist BNF also induced CYP1A1 in cells from both populations, although with only a 3-fold difference in sensitivity (NBH < SC). These results indicate that chronic exposure to high levels of HAHs has led to a reduction in the sensitivity of NBH killifish to AhR agonists. The resistance is systemic and pretranslational, and exhibits compound-specific differences in magnitude. These findings suggest an alteration in the AhR signal transduction pathway in NBH fish.
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PMID:Acquired resistance to Ah receptor agonists in a population of Atlantic killifish (Fundulus heteroclitus) inhabiting a marine superfund site: in vivo and in vitro studies on the inducibility of xenobiotic metabolizing enzymes. 1122 75

Butyrate, one of the major products of gut fermentation, is known to inhibit proliferation, induce apoptosis and differentiation, and increase phase II enzyme activities in tumor cells, whereas little information is available on protective effects in less-transformed colon cells. The aim of this study was to investigate whether the chemoprotective mechanism of glutathione S-transferase (GST) induction by butyrate could also play a role in earlier stages of colon carcinogenesis and whether chemoresistance of cells toward the endogenous genotoxic risk factor 4-hydroxy-2-nonenal (HNE) could be a consequence of butyrate treatment. As cell models, we used the human tumor cell lines HT29 and HT29 clone 19A, a differentiated subclone with properties resembling primary colon cells. We determined the expression of GSTP1 protein (enzyme-linked immunosorbent assay), the major GST in HT29, GSTP1 mRNA (Northern blotting), GST activity, intracellular glutathione, and total protein. The genotoxic impact of HNE (100-200 microM) was compared in butyrate-treated and nontreated cells using single-cell microgel electrophoresis. Our results show that GSTP1 mRNA, GSTP1 protein, GST activity, and total protein were increased (1.2- to 2.5-fold) and glutathione levels were maintained after 24-72 h of incubation with 4 mM butyrate. Moreover, a marked reduction of HNE-induced genotoxicity was caused by preincubation with butyrate. Butyrate also induced the phosphorylation of extracellular signal-regulated kinases (ERK1/2, Western blotting) after 5-30 min, which indicates a regulation of GST expression by this signal pathway. Most effects were greater in HT29 parent cells than in clone cells. In conclusion, butyrate enhances expression of GST and other proteins in both cell lines, which leads to an enhanced chemoprotection, reducing the impact of HNE genotoxicity. Thus butyrate could play a role in early and later stages of cancer prevention by reducing exposure to relevant risk factors.
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PMID:Butyrate induces glutathione S-transferase in human colon cells and protects from genetic damage by 4-hydroxy-2-nonenal. 1209 19

o-Nitrotoluene and o-toluidine hydrochloride are structurally related chemicals that are suspected and demonstrated animal carcinogens, respectively. The metabolic potential of the gastrointestinal flora is considered an important factor in o-nitrotoluene-induced toxicity and involves the reduction of the nitro group to the corresponding amine (forming o-toluidine). These studies were designed to 1) compare the target organ toxicities of o-nitrotoluene and o-toluidine hydrochloride administered in feed at approximately equimolar doses (5,000 ppm) to male F344/N rats for 13 or 26 weeks, 2) determine the potential progression or reversibility of toxic or proliferative lesions following chemical withdrawal (stop-exposure) for 13 weeks after 13 weeks of exposure, and 3) examine the effect of antibiotic-altered gastrointestinal flora on the toxicity and/or carcinogenicity of o-nitrotoluene. o-Nitrotoluene and o-toluidine hydrochloride caused mesothelial hyperplasia and mesothelioma in male rats after 13 or 26 weeks of dietary exposure. The incidence of mesothelioma was greater and the latency was less in rats administered o-nitrotoluene than in rats administered o-toluidine hydrochloride. Additionally, o-nitrotoluene caused testicular degeneration in rats. Effects of o-nitrotoluene administration in the liver included progressive, irreversible increases in liver weight and irreversible increases in the incidences of cytoplasmic vacuolization and oval-cell hyperplasia. Placental glutathione S-transferase (PGST)-positive foci of cellular alteration occurred in the liver after 13 weeks of o-nitrotoluene exposure, and the number and size (as reflected by the volume fraction) of foci were increased after 26 weeks of continuous exposure. During the recovery period, the number of PGST-positive foci in rats in the stop-exposure group decreased slightly, but the size of the foci continued to increase. After 26 weeks, cholangiocarcinoma occurred in 2 of 20 rats in the stop-exposure group and 1 of 20 rats in the continuous-exposure group administered o-nitrotoluene. In contrast, liver effects in rats administered o-toluidine hydrochloride consisted of minimal hemosiderin accumulation in Kupffer cells; the incidence of this lesion in the stop-exposure group decreased during the recovery period. o-Toluidine hydrochloride caused fewer and much smaller PGST-positive foci than those caused by o-nitrotoluene. o-Nitrotoluene caused an accumulation of hyaline droplets in the renal tubule epithelium; this accumulation did not increase in severity with continued exposure and completely regressed during the recovery period. Exposure to o-toluidine hydrochloride did not cause hyaline droplet accumulation but did cause an accumulation of hemosiderin pigment in renal tubule epithelium. This change progressed in severity during the 26-week continuous-exposure study but decreased in severity in the stop-exposure study during the recovery period. Exposure to o-nitrotoluene or o-toluidine hydrochloride caused increased incidences of hematopoiesis, hemosiderin accumulation, and capsular fibrosis in the spleen. In rats administered o-toluidine, spleen effects were much more prominent and were also reflected by congestion and markedly increased spleen weights. During the recovery period for the stop-exposure groups administered either compound, incidences of hemosiderin accumulation and hematopoiesis were decreased, but the capsular fibrosis did not resolve. Hyperplasia of the transitional epithelium in the urinary bladder was observed only in rats administered o-toluidine hydrochloride; this lesion did not increase in severity after 26 weeks of continuous exposure and completely regressed in the stop-exposure group during the recovery period. Alteration of the gastrointestinal flora by daily gavage administration of antibiotics did not affect the pattern or severity of toxicity at any site or the development of mesothelioma in rats exposed to o-nitrotoluene, although cholangiocarcinomas that occurred in three rats with the normal flora did not occur in groups with the altered intestinal flora. Subsequent studies determined that the antibiotic regimen used was effective only in reducing the gut population of aerobic microorganisms and had little effect on obligate anaerobes, which are thought to play a mayor role in nitro group reduction. In summary, these studies confirmed the target organs and compared the relative toxicity for o-nitrotoluene and o-toluidine hydrochloride administered to male F344/N rats at equimolar concentrations in feed. With the exception of the spleen toxicity observed with each chemical, but more prominently with o-toluidine hydrochloride, morphologic effects of exposure to each of these chemicals in the testis/epididymis, liver, kidney, and urinary bladder were different. The results of these studies demonstrate the somewhat greater relative carcinogenic potential of o-nitrotoluene compared to o-toluidine hydrochloride after 13 or 26 weeks of administration based on the occurrence of mesothelioma and cholangiocarcinoma. The apparently lower potency of o-toluidine hydrochloride relative to o-o-nitrotoluene in the induction of mesothelioma suggests that simple intestinal reduction of the nitro group may not be sufficient for carcinogenic activity in the mesothelium.
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PMID:NTP Comparative Toxicity and Carcinogenicity Studies of o-Nitrotoluene and o-Toluidine Hydrochloride (CAS Nos. 88-72-2 and 636-21-5) Administered in Feed to Male F344/N Rats. 1211 63

Graminivorous species of grasshoppers develop lethal lesions in their midgut epithelia when they ingest tannic acid, whereas polyphagous grasshoppers are unaffected by ingested tannins. This study tests the hypothesis that polyphagous species are defended by higher activities of antioxidant enzymes (constitutive or inducible) in their guts than are graminivorous species. Comparisons were made between four antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APOX), and glutathione transferase peroxidase (GSTPX). Enzyme activities were measured in the gut lumens and midgut tissues of Melanoplus sanguinipes (polyphagous) and Aulocara ellioti (graminivorous). The results of this study do not support the hypothesis that M. sanguinipes is better defended by antioxidant enzymes than is A. ellioti, nor are these enzymes more inducible in M. sanguinipes than in A. ellioti when insects consume food containing 15% dry weight tannic acid. Instead, tannic acid consumption reduced SOD, APOX, and GSTPX activities in both species. This study reports the first evidence that SOD is secreted into the midgut lumen in insects, with activities two- to fourfold higher than those found in midgut tissues. The spatial distribution of GSTPX and APOX activities observed in both species suggests that ingested plant antioxidant enzymes may function as acquired defenses in grasshoppers. In addition, the results of this study permit the first comparison between the antioxidant enzyme defenses of Orthoptera and Lepidoptera. Most notably, grasshoppers have higher SOD activities than caterpillars, but completely lack APOX in their midgut tissues.
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PMID:Gut-based antioxidant enzymes in a polyphagous and a graminivorous grasshopper. 1219 99

The glutathione S-transferases (GSTs) are a multigene family of enzymes largely involved in the detoxification of chemicals. In animals, enhanced expression is mediated by products of gut fermentation. Of these, butyrate induces GSTP1 protein expression and GST activity in the human colon tumor cell line HT29. The aim of the following investigations was to further elucidate butyrate-modulated induction of additional colonic GSTs in HT29 and to determine baseline expression in non-transformed cells, isolated from human colorectal tissue. We measured five GST protein subunits (GSTA1/2-composed of GST A1-1, A1-2 and A2-2-GSTM1, GSTM2, GSTP1, GSTT1) by western blot, GST activity using 1-chloro-2,4-dinitrobenzene as substrate and GSTM2 mRNA expression with RT-PCR. GSTP1, followed by GSTT1, were major subunits in all colon cells. Cells isolated from colon tissue were identified to be colonocytes and colon fibroblasts, both of which also expressed substantial levels of GSTM1 and GSTM2. The inter-individual variation of GST subunits in coloncytes of 15 individuals was marked, with total GST protein per 106 cells differing by more than a factor of four. In HT29, butyrate significantly enhanced GSTA1/2 (3.5-fold), GSTM2 (not detectable in controls), GSTP1 (1.5-fold) and GST activity (1.4-fold), but not GSTM1 or GSTT1. GSTM2 mRNA expression was significantly induced after 24 ( approximately 14-fold) and 72 h treatment ( approximately 8-fold). In colon fibroblasts, butyrate (4 mM, 72 h) also induced GSTM2 protein (1.7-fold) and GST activity (1.4-fold). Colonocytes were too short lived to be used for inducibility studies. In conclusion, GSTs are expressed with high inter-individual variability in human colonocytes. This points to large differences in cellular susceptibility to xenobiotics. However, butyrate, an important luminal component produced from fermentation of dietary fibers, is an efficient inducer of GSTs and especially of GSTM2. This indicates that butyrate may act chemoprotectively by increasing detoxification capabilities in the colon mucosa.
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PMID:Expression of glutathione S-transferases (GSTs) in human colon cells and inducibility of GSTM2 by butyrate. 1289 3


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