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)

The human placenta oxidizes several xenobiotics, although the spectrum of substrates and metabolic activities when compared with the liver appears restricted. Maternal cigarette smoking or PCB exposure increase the expression of CYP1A1. This induced activity is able to catalyze the activation of benzo(a)pyrene into DNA-bound adducts, both in vitro and in vivo. Studies with RT-PCR technique have demonstrated that first trimester placentae express at the mRNA level CYP1A1, 1A2, 2C, 2D6, 2E1, 2F1, 3A4, 3A5, 3A7 and 4B1 and at full term CYP1A1, 2E1, 2F1, 3A3/4, 3A5 and 3A7. However, more detailed studies on cDNA probes or with specific antibodies or 'diagnostic' substrates for other than CYP1A1, 2E1 and 3A gene products have yielded negative results. Studies on human placenta and a chorioncarcinoma cell line, JEG 3 cells, boulster the concept that placental CYP1A1 and 1B1 - although their expression is Ah receptor and ARNT mediated - is controlled by distinct mechanisms. Aromatase, CYP19, and cholesterol side-chain cleaving, CYP11B, genes, proteins and activities are catalytically active in human placentae throughout the pregnancy and those parameters do not seem to be affected by maternal cigarette smoking but rather maternal health status. However, the substrate binding pocket of aromatase accepts as its substrate several xenobiotics and is responsible for constitutive xenobiotic biotransformations.Functional placental glutathione S-transferase, N-acetyl transferase and epoxide hydrolase are expressed via one gene each and their function reflects the placenta as an endocrine organ rather than a xenobiotic-metabolizing unit. However, markers for oxidative stress can be detected in decreased glutathione S-transferase activities.Because human placenta has quite well defined metabolic characteristics, and obtaining placental samples will not meet any drastic ethical difficulties, it could be used more intensively as a source of metabolizing enzymes in in vitro studies during the course of a drug development program. The human placenta, or its subcellular organelles, could serve as a real alternative model for an extrahepatic tissue in replacing recombinant expression systems especially if CYP11, 19, 1A1 or potentially 2E1 are target enzymes for potential metabolic interactions.
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PMID:The expression and regulation of drug metabolism in human placenta. 1083 48

This study evaluates and quantifies the interactive hepatic tumor promoting effects of two PCBs, the Ah receptor agonist PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the constitutive androstane receptor (CAR) agonist PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl). Promotion of altered hepatic foci was evaluated utilizing a medium-term 8-week bioassay for promoters of hepatocarcinogenesis. The assay employs placental glutathione-S-transferase positive (GST-P+) liver cell foci as markers of preneoplasia in female Fischer 344 rats treated with the known initiator diethylnitrosamine followed by partial hepatectomy and by gavage exposure to test chemicals. GST-P+ foci were quantified by histomorphometry and were reported as areas and numbers of GST-P+ foci within the area of liver examined. For PCB 126, the doses were 0.1, 1.0, and 10 microg/kg body weight. For PCB 153, the doses were 10, 100, 1000, 5000, and 10,000 microg/kg body weight. Combined PCB 126 and 153 exposures were 0.1 + 10, 1 + 100, 10 + 1000, 10 + 5000, and 10 + 10,000 microg/kg, respectively. Individual PCB treatment resulted in dose dependent increases in liver and adipose concentrations. Hepatic PCB 153 levels were significantly increased (p < 0.01) after combined exposure. Treatment with PCB 126 or PCB 153 alone resulted in a significant (p < 0.01) dose dependent increase in GST-P+ foci area and number compared with controls. Treatment with the mixture of PCB 126 and 153 resulted in antagonistic GST-P+ focus formation (p < 0.001) for both foci area and number. The less than additive effect was present at all 5 PCB 126/PCB 153 dose combinations, including the low doses of PCB 126 and 153 that did not show significant promotional activity alone.
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PMID:Nonadditive hepatic tumor promoting effects by a mixture of two structurally different polychlorinated biphenyls in female rat livers. 1186 72

The glutathione S-transferases from the northern quahog (Mercenaria mercenaria) from control and contaminated sites were subjected to incubation with polychlorinated biphenyls in an Aroclor 1248 mixture. Subsequent solvent-solvent extraction and gas chromatographic analysis revealed that 2 of the 28 congeners present in the Aroclor 1248 mixture were affected by the presence of the GST. The first of the aforementioned congeners with a retention time of 36.7 min by gas chromatographic analysis decreased in total content. The largest decrease in the 36.7 min peak was the result of incubation with GSTs purified from quahogs taken from the Superfund site in New Bedford Harbor, New Bedford, MA. The second of the affected congeners with a retention time of 59 min showed an increase, which could result from the glutathione conjugation to the PCB congener. The Aroclor 1248 mixture (a limited number of its constituent congeners) also acts as a competitive inhibitor of the GST activity, which is indicative of a substance interacting with the free GST in solution. The ultimate result of the conjugation of the PCB congener to GSH would be the formation of a hydrophillic conjugate of an otherwise insoluble PCB. The PCB-GSH conjugating activity of the quahog GSTs may ultimately serve as a tool for PCB remediation.
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PMID:An enzyme based dechlorination of a polychlorinated biphenyl (PCB) mixture, Aroclor 1248, using glutathione S-transferases from the northern quahog Mercenaria mercenaria. 1367 2

2,3,3',4,4'-Pentachlorobiphenyl, PCB-105 (IUPAC no. 105) was orally administered twice with a 4-day interval between dosings (total dose 10 mg kg(-1) body weight) to gonadally immature cod and rainbow trout of both sexes. The fish were killed 9 and 17 days after the first treatment, and the effects of PCB-105 on hepatic xenobiotic metabolising enzymes were determined by examining the cytochrome-P450-dependent ethoxyresorufin-O-deethylase (EROD) and aldrin epoxidase activities, and the EROD-catalysing P450 1A1 protein by indirect enzyme-linked immunosorbent assay (ELISA). Glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene was included. The hepatic levels of the compound were determined. In addition, the distribution patterns of radio-labelled PCB-105 were studied by whole-body autoradiography. In exposed rainbow trout EROD activity and P450 1A1 by enzyme linked immunosorbent assay (ELISA) were significant induced, while GST activity was significant reduced. Exposed cod did not show significantly different enzyme values from controls, but percentage fat in the liver was significantly reduced. The whole cod liver contained about 1000 times more PCB-105 than the corresponding trout liver, and on a fat-weight basis the PCB level was five to six times higher in cod liver than in the rainbow trout liver. The autoradiographical investigation revealed high concentrations of radiolabelled compound in the liver and the brain of cod, while in rainbow trout the radiolabel was mainly confined to extrahepatic fat depots. These results demonstrate that the mono-ortho chlorinated coplanar analogue, PCB-105, has a different distribution pattern in the two fish species and that the potential for induction of the hepatic xenobiotic metabolising enzyme system seems to be lower in the cod than in the rainbow trout.
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PMID:Tissue distribution and effects on hepatic xenobiotic metabolising enzymes of 2,3,3',4,4'-pentachlorobiphenyl (PCB-105) in COD (Gadus morhua) and rainbow trout (Oncorhynchus mykiss). 1509 67

The sensitivity of carp to chronical stress due to single and combined mixtures (each 50%) of TBT and PCB was evaluated under laboratory conditions. And concluded, mixed exposures were partially more or less toxic than single ones. Xenobiotic stress led to both decreased mean daily swimming speed and an increased mean swimming speed during darkness. Also a decreased preferred swimming depth (nearer to the surface) during nighttime was observed. We found approximately synergistic effects of TBT and PCB in swimming behavior of carp exposed to those mixtures. PCB did not affect the body growth significantly, TBT-stress led to a decreased body growth and the exposure to PCB-TBT mixture caused an approximately additive decrease of body growth. Measurement of biotransformation potential measured as GST enzyme activity showed both increasing or decreasing activity levels after exposure to single and mixture chemical combinations (approximately additive, antagonistic and synergistic). Nevertheless, we had to conclude that all methods tested were useful to screen subacute effects of single as well as mixed xenobiotic chemicals on carp, which is the prerequisite for an investigation of samples taken from the environment.
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PMID:Impact of PCB mixture (Aroclor 1254) and TBT and a mixture of both on swimming behavior, body growth and enzymatic biotransformation activities (GST) of young carp (Cyprinus carpio). 1564 31

In this study, the effect of dietary vitamin E on the hepatic tumor-promoting activity of PCB-77 and PCB-153 in female Sprague-Dawley rats (175-200 g) was investigated. One week after diethylnitrosamine injection, rats were fed purified diets containing 10, 50, or 250 mg/kg vitamin E in the form of alpha-tocopheryl acetate. Starting 1 wk later, we injected rats i.p. with vehicle (corn oil) or PCB-77 or PCB-153 (300 mumol/kg) every 14 d for 4 injections. All rats were killed 10 d after the last PCB injection. The number and volume of placental glutathione S-transferase (PGST)-positive foci were increased by PCB-77 but not by PCB-153. Vitamin E did not affect the induction of PGST-positive foci. PCB-77, but not PCB-153, increased hepatic NF-kappaB activity. In conclusion, dietary vitamin E supplementation does not protect against the induction of altered hepatic focal lesions by PCBs.
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PMID:Dietary vitamin E does not inhibit the promotion of liver carcinogenesis by polychlorinated biphenyls in rats. 1567 Dec 27

The bphK gene encoding glutathione S-transferase (GST) is located in the bph operon (PCB co-metabolism) in Burkholderia sp. strain LB400 and the enzyme has recently been shown to have dechlorination activity in relation to 4-chlorobenzoate (4-CBA). Alignments using other glutathione S-transferase sequences found in PCB degradation operons identified a highly conserved region in the C-terminal domain of these enzymes that included a conserved motif implicated in protein folding in eukaryotic GSTs. Site-directed mutagenesis indicated that the region is indirectly involved in the catalytic activity and substrate specificity of BphK. Predicted hydrogen bond interactions involving Asp155 play an important role in the enzymatic properties of this glutathione S-transferase.
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PMID:Analysis of the C-terminal domain of Burkholderia sp. strain LB400 BphK reveals a conserved motif that affects catalytic activity. 1600 62

To investigate the impacts of marine pollution on aquatic organisms, we tested the intertidal copepod Tigriopus japonicus as a model species. To analyze the copepods' responses to endocrine-disrupting chemicals (EDCs), we exposed them to two different chemicals: 4,4'-octylphenol (4,4'-OP, 12.5-100 microg/L for 2 h) and polychlorinated biphenyl (PCB, 6.25-25 microg/L for two days). 4,4'-OP was toxic, although exposure time was limited to 2h. After extracting total RNA from the exposed T. japonicus, we performed reverse transcriptase-polymerase chain reaction (RT-PCR) to determine gene expression patterns following chemical exposure. To analyze the gene expression of T. japonicus, we used glutathione S-transferase with GAPDH as an internal control. Of the genes tested using EDC-exposed samples, 4,4'-OP induced upregulation of the glutathione S-transferase (GST) gene, while PCB caused downregulation of the GST gene. These results suggest that the two EDCs act in different manners in T. japonicus.
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PMID:Cloning and characterization of glutathione S-transferase gene in the intertidal copepod Tigriopus japonicus and its expression after exposure to endocrine-disrupting chemicals. 1672 91

Mytilus galloprovincialis mussels from a clean area were transplanted from 2003 to 2005 to several stations in the Bay of Cannes (North-Western Mediterranean Sea) including a site considered as reference, for 1 month at the end of spring (May). Several biomarkers (AChE, GST and CAT activities, TBARS and MT concentrations) were measured in the transplanted organisms. The concentrations of metals (Cd, Cu and Zn) were determined in the transplanted mussels, PAH and PCB analyses were performed in the mussels caged in 2004. The integrated biomarker response (IBR) was calculated; pollutant concentrations in mussels were displayed as star plots and compared to IBR star plots. Visualization was thus possible between sites for comparison with exposure conditions. Results demonstrated that the mussels from the Old harbour site (VP) are characterized by elevated copper and PCB concentrations, those from Canto harbour (PC) presented high PCB contents and those from the mouth of the Siagne River (ES) high PAH concentrations compared to the animals transplanted in the reference site (IL). In 2003, there was a visual correlation between the copper gradient measured in the transplanted mussels and the IBR variation. In 2004, the agreement between the copper gradient and the PCB gradient measured in the caged mussels and the IBR variation was good whereas the PAH gradient did not seem to contribute to the IBR demonstrating that the chosen biomarkers did not respond to PAHs. In 2005, IBR showed that other contaminants, not measured might be present in VP, PC and ES compared to the reference station (IL).
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PMID:Integrated biomarker response index as a useful tool for environmental assessment evaluated using transplanted mussels. 1682 46

Hydroxylated metabolites of PCBs [OH-PCBs] represent new health and environmental concern because they have been shown to have agonist or antagonist interactions with hormone receptors (HRs) or hormone-receptor mediated responses. The present study was designed to investigate the estrogenic potency based on anti-AhR signalling effect of three 4-OH substituted PCB congeners (#107, #146 and #187), one 3-OH substituted congener (#138), and the pharmaceutical synthetic estrogen, ethynylestradiol (EE2) in fish in vitro system using primary culture of Atlantic salmon hepatocytes. The effects were studied by quantifying changes in transcripts with gene-sequence primer pairs for a suite of gene responses (AhRalpha, ARNT, CYP1A1, CYP3A, UGT and GST) belonging to the xenobiotic biotransformation system. Our data show that OH-PCB congeners and EE2, decreased AhRalpha and ARNT transcript levels, and CYP1A1, UGT and GST gene expressions, together with CYP3A gene expression. The decreased expression of transcripts for xenobiotic biotransformation system is related to the concentration of individual OH-PCB congener and these responses are typical of reported estrogenic and estrogen-like effects on the CYP system. Modulation of biotransformation pathways by OH-PCBs may alter xenobiotic metabolism leading to the production of toxic reactive molecules, altering pharmacokinetics and diminishing the clearance rate of individual chemicals from the organism.
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PMID:Effects of hydroxy-polychlorinated biphenyl (OH-PCB) congeners on the xenobiotic biotransformation gene expression patterns in primary culture of Atlantic salmon (Salmo salar) hepatocytes. 1720 28


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