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)

Benzo[a]pyrene diol epoxide (BPDE)-DNA adducts are involved in the induction of p53 mutations and probably in the causation of human lung cancer associated with cigarette smoking. The ratio between CYP1A1 and GST enzyme activities is a critical determinant of the target dose of carcinogenic BPDE and other DNA-reactive PAH metabolites. In this review, we summarize the published data on modulation of (+)-anti-BPDE-DNA adduct levels in smokers' lungs by CYP1A1*2 genotypes alone or in combination with GSTM1 polymorphism and compare these results with those reported for aromatic/hydrophobic (bulky) DNA adducts. The data published so far show only a trend for a non-significant increase in bulky DNA adduct levels in subjects with GSTM1*0 or the CYP1A1*2-GSTM1*0 genotype combination. In contrast, a clear dependence of (+)-anti-BPDE-DNA adduct levels was found as a function of the CYP1A1 and GSTM1 genotypes: In lung parenchyma, this adduct was more pronounced in persons with the GSTM1*0 genotype, and CYP1A1*2-GSTM1*0 carriers had higher (+)-anti-BPDE-DNA adduct levels than those with CYP1A1*1/*1-GSTM1*0. The homozygous CYP1A1*2/*2 carriers in the GSTM1*0 group had the highest (+)-anti-BPDE-DNA adduct levels. Our analysis leads to the conclusion that the risk-modifying effects of metabolic genotypes and of gene interactions might be more easily identifiable if specific markers of structurally defined adducts were used, such as the (+)-anti-BPDE-DNA adduct. These results are also consistent with the hypothesis that BP (PAH) induce G:C to T:A transversion mutations in the hotspot codons of the p53 tumor suppressor gene and are thus involved in malignant transformation of the lung tissue of smokers.
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PMID:CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation. 1250 20

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1*0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.
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PMID:Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes. 1287 24

Anguilla anguilla L. were caged for 8 and 48 h in harbor water of Aveiro Lagoon, Portugal. Respiratory burst activity (RBA) of peritoneal, head kidney, and gill phagocytes was measured. Lipid peroxidation (LPO) was estimated in gill, kidney, and liver. Liver ethoxyresorufin-O-deethylase (EROD) activity, cytochrome P450 (Cyt P450) content, and bile metabolites were assayed. Various antioxidant enzymes, viz., glutathione peroxidase, catalase, and glutathione S-transferase and nonenzymatic antioxidant, viz., total reduced glutathione were also studied. Harbor water xenobiotics induced a significant RBA increase in gill after 8 h; whereas in peritoneum and head kidney it increased after 48 h exposure. These responses were adversely associated with tissue-specific peroxidative damage since significant LPO increase was observed in gill (8 and 48 h), kidney (48 h), and liver (48 h). The tissue most affected was gill. Moreover, liver EROD activity, Cyt P450 content and bile metabolites remain unaltered after 8 h; in contrast, 48 h exposure showed significant EROD activity decrease and pyrene-type bile metabolites increase. Decreased EROD activity may be associated with concomitant liver damage, as increased LPO was observed after 48 h. Furthermore, the tissue-specific damage corresponded to the differences in the antioxidant potentials of the tissues, since the initial exposure period caused a significant increase in liver antioxidant activities, whereas gill and kidney showed a significant decrease, demonstrating that liver is highly adaptive to oxidative damage. However, at 48 h exposure gill, kidney, and liver showed a suppressive antioxidant effect, probably due to PAHs, since a significant induction at PAH-type bile metabolites has been seen. Our results demonstrate that phagocyte activation and associated peroxidative damage are concomitantly corroborated with enzymatic and nonenzymatic antioxidant activity differences. In addition, hepatic antioxidant induction after short-term exposure may serve as a potent biomarker for water pollutants in fish.
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PMID:Enzymatic and nonenzymatic antioxidants as an adaptation to phagocyte-induced damage in Anguilla anguilla L. following in situ harbor water exposure. 1504 Dec 52

People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic or mutagenic properties in experimental systems. Exposure can occur exogenously when these agents are present in food, air or water, and also endogenously when they are products of metabolism or pathophysiologic states such as inflammation. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers, when exposures are related to "life-style" factors such as diet, tobacco use, etc. This chapter summarizes several aspects of environmental chemical carcinogenesis that have been extensively studied and illustrates the power of mechanistic investigation combined with molecular epidemiologic approaches in establishing causative linkages between environmental exposures and increased cancer risks. A causative relationship between exposure to aflatoxin, a strongly carcinogenic mold-produced contaminant of dietary staples in Asia and Africa, and elevated risk for primary liver cancer has been demonstrated through the application of well-validated biomarkers in molecular epidemiology. These studies have also identified a striking synergistic interaction between aflatoxin and hepatitis B virus infection in elevating liver cancer risk. Use of tobacco products provides a clear example of cancer causation by a life-style factor involving carcinogen exposure. Tobacco carcinogens and their DNA adducts are central to cancer induction by tobacco products, and the contribution of specific tobacco carcinogens (e.g. PAH and NNK) to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach. Factors considered include presence in tobacco products, carcinogenicity in laboratory animals, human uptake, metabolism and adduct formation, possible role in causing molecular changes in oncogenes or suppressor genes, and other relevant data. This approach can be applied to evaluation of other environmental carcinogens, and the evaluations would be markedly facilitated by prospective epidemiologic studies incorporating phenotypic carcinogen-specific biomarkers. Heterocyclic amines represent an important class of carcinogens in foods. They are mutagens and carcinogens at numerous organ sites in experimental animals, are produced when meats are heated above 180 degrees C for long periods. Four of these compounds can consistently be identified in well-done meat products from the North American diet, and although a causal linkage has not been established, a majority of epidemiology studies have linked consumption of well-done meat products to cancer of the colon, breast and stomach. Studies employing molecular biomarkers suggest that individuals may differ in their susceptibility to these carcinogens, and genetic polymorphisms may contribute to this variability. Heterocyclic amines, like most other chemical carcinogens, are not carcinogenic per se but must be metabolized by a family of cytochrome P450 enzymes to chemically reactive electrophiles prior to reacting with DNA to initiate a carcinogenic response. These same cytochrome P450 enzymes--as well as enzymes that act on the metabolic products of the cytochromes P450 (e.g. glucuronyl transferase, glutathione S-transferase and others)--also metabolize chemicals by inactivation pathways, and the relative amounts of activation and detoxification will determine whether a chemical is carcinogenic. Because both genetic and environmental factors influence the levels of enzymes that metabolically activate and detoxify chemicals, they can also influence carcinogenic risk. Many of the phenotypes of cancer cells can be the result of mutations, i.e., changes in the nucleotide sequence of DNA that accumulate as tumors progress. These can arise as a result of DNA damage or by the incorporation of non-complementary nucleotides during DNA synthetic processes. Based upon the disparity between the infrequency of spontaneous mutations and the large numbers of mutations reported in human tumors, it has been postulated that cancers must exhibit a mutator phenotype, which would represent an early event in cancer progression. A mutator phenotype could be generated by mutations in genes that normally function to guarantee genetic stability. These mutations presumably arise via DNA damage by environmental or endogenous agents, but it remains to be determined whether the acquisition of a mutator phenotype is a necessary event during tumor progression.
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PMID:Environmental and chemical carcinogenesis. 1548 40

Marine mussels Mytilus sp. were transplanted on a monthly basis in cages over one year to oyster farms and harbours in the Arcachon Bay (France) in order to assess the water quality of the bay. Contaminant levels (organotin compounds, trace metals, PCBs and PAHs) were measured in tissues of transplanted mussels and mussels from a reference station, along with physiological parameters of the mussels (condition indexes, lipid content and dry weight). Four biomarkers (AChE: acetylcholinesterase activity, GST: gluthathione S-transferase activity, CAT: catalase activity and TBARS: thiobarbituric acid-reactive substance content) were also monitored. The remote stations monitored (oyster parks) exhibited no accumulation pattern of pollutants. Their respective concentrations therefore constitute a background level of the contamination in the bay ([TBT]= 30 ng Sn g(-1) dw, [SigmaHAPs]= 100 ng g(-1) dw, [SigmaPCBs]= 35 ng g(-1) dw). The elevated chemical contamination of the largest harbour of the bay, the Arcachon harbour, can be interpreted in terms of persistence of organotin compounds ([SigmaOTs]= 1500-2000 ng Sn g(-1) dw) and PAHs ([SigmaHAPs]= 4500-5000 ng g(-1) dw) in sediments and, to a lesser extent, of direct inputs of copper ([Cu]= 20 microg g(-1) dw in harbours versus 7 in oyster parks) and petrogenic PAHs ([methylphenanthrenes]= 1600 ng g(-1) dw in the dockyard versus 170 at the gas stations), related to the use of copper-based antifouling paints and to dockyard activity, respectively. However, the Arcachon Bay presents a low contamination level by PCBs and metals, including harbour stations. Furthermore, higher levels of other PAHs (particularly alkyl PAHs such as methylphenanthrenes/1600 ng g(-1) dw) not included in the 16 PAHs from the EPA priority list (usually studied in biomonitoring programmes/1500 ng g(-1) dw) in the Arcachon harbour underline the need to integrate these compounds in biomonitoring of highly PAH-polluted areas such as harbours in order to avoid misinterpretation of the biological responses observed. Biomarker responses were not able to discriminate the different chemical contamination levels recorded in the Arcachon Bay and rather reflected changes in environmental factors. Furthermore, the strong intraspecies variability of biological responses could be due to genetic differences of mussels from the Arcachon Bay. It is the first time that such an integrated monitoring is performed in the Arcachon Bay, also taking into account seasonal variations of chemical contents and biomarkers levels in mussel tissues.
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PMID:One-year monitoring survey of organic compounds (PAHs, PCBs, TBT), heavy metals and biomarkers in blue mussels from the Arcachon Bay, France. 1573 81

The redox cycling of heavy metals as well as their interactions with organic pollutants is a major contributor to the oxidative stress resulting from aquatic pollution. Therefore, in order to evaluate beta-naphthoflavone (BNF), Cu and BNF/Cu-induced oxidative stress with single and subsequent exposures, research was carried out in European eel (Anguilla anguilla L.). Eel gill and kidney oxidative stress biomarker responses such as lipid peroxidation (LPO), glutathione peroxidase (GPX), catalase (CAT), glutathione S-transferase (GST) and total reduced glutathione (GSH) to a single 24 h exposure to two copper concentrations (Cu-1 microM, 2.5 microM) and BNF (2.7 microM) with or without 24 h BNF (2.7 microM) pre-exposure were investigated. Cu exposure alone showed a significant gill GST increase at the lowest concentration and GSH content decrease for the highest concentration. Double BNF exposure in gill demonstrated a significant increase in LPO, CAT, GPX and GST, as well as a decrease in GSH content. However, in sequential BNF/Cu exposures, only the highest Cu concentration exhibited a significant increase in LPO and GSH as well as a decrease in GPX (vs. BNF + CW). In kidney, Cu exposure alone showed a significant CAT and GSH contents decrease for both concentrations, and at highest concentration in GPX; as well as GST increase at the lowest concentration. Double BNF exposure showed a significant increase in LPO and GST. Nevertheless, in sequential BNF/Cu exposures, both concentrations exhibited a significant increase in LPO and decrease in GSH contents. Moreover, LPO was also increased significantly in comparison to BNF+CW and the equivalent Cu exposures without BNF pre-exposure. Concerning GPX, a significant increase was observed at highest Cu concentration. In GST, a significant decrease at the lowest Cu concentration and increase at the highest Cu concentration was observed. Summarizing, a simple copper or BNF exposures have no ability to induce LPO in both gill and kidney. However, double BNF exposure induced LPO in both organs and sequential BNF/Cu exposures potentiated the risk of peroxidative damage occurrence in both organs. BNF/Cu interference on antioxidant responses differs between the studied organs. In gill, antagonistic effects were denoted with probable reflex in terms of peroxidative damage increase. In kidney, BNF pre-exposure prevented CAT and GPX inhibition by copper; though, no advantage of this effect was perceptible as defence against LPO generation. Considering BNF as a surrogate for a PAH and the detected interactions with copper, as well as the likelihood that these effects would be observed in polluted ecosystems, current results demonstrate their relevance to actual ecological exposures contributing to a better knowledge on oxidative stress mechanisms in fish.
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PMID:Anguilla anguilla L. oxidative stress biomarkers responses to copper exposure with or without beta-naphthoflavone pre-exposure. 1616 50

A bacterium (designated strain ZX4) able to degrade poly aromatic hydrocarbons was isolated from oil-contaminated soil. Based on analysis of the 16S rDNA sequence, whole cell fatty acid, and Biolog-GN, the strain was identified as Sphingomonas paucimobilis. The detection of GST (Glutathione S-transferase) indicated that the GST from the strain had the activity of conjugating with CDNB and it maybe relate with degradation of PAHs. The PCR product of GST gene from the strain confirmed its presence. Phylogeny analysis based on gst sequence indicated that the strain was relatively close with the strain which can degrade PAH likewise.
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PMID:[Identification, cloning and sequencing of GST gene of bacterium degrading poly-aromatic hydrocarbons]. 1627 87

Fish in the aquatic environment can be subjected to a multipollution state and the occurrence of sequential exposures is an important aspect of eco-toxicological research. In this context, a preceding exposure can affect a toxic response to a subsequent exposure. Therefore, the current study was based on sequential exposures, viz. to a PAH-like compound (beta-naphthoflavone, BNF) followed by a heavy metal (chromium, Cr), focusing on the assessment of oxidative stress responses and their role in induction of genotoxicity. Oxidative stress responses in gill and kidney were investigated in European eel (Anguilla anguilla L.), and measured as lipid peroxidation (LPO), glutathione peroxidase (GPX), catalase (CAT) and glutathione S-transferase (GST) activity, and reduced glutathione (GSH) concentration, whereas genotoxicity was measured as DNA strand breakage. Fish were exposed for 24 h to two Cr concentrations (100 microM, 1 mM), with or without pre-exposure to BNF (2.7 microM, 24 h). In gill, a GSH decrease was observed along with loss of DNA integrity at all exposure conditions except at the lowest Cr concentration, showing a crucial role of GSH over genotoxicity. Moreover, sporadic induction of antioxidant enzymes was not effective in the protection against genotoxicity. However, a different mechanism seems to occur in kidney, since the loss of DNA integrity detected for all exposed groups was not accompanied by alterations in antioxidant levels. With regards to peroxidative damage, both organs showed an LPO increase after sequential exposure to BNF and 100 microM Cr. However, no association between LPO induction and antioxidant responses could be established, showing that LPO is not predictable solely on the basis of antioxidant depletion. The interference of BNF pre-exposure with the response of organs to Cr showed a marked dependence on the Cr concentration. Gill showed synergistic effects on LPO and GPX increase, as well as on CAT and GSH decrease for the lowest Cr concentration. However, for the highest concentration an additive effect on decrease of DNA integrity and an antagonistic effect on the increase of GPX were observed. In kidney, synergistic effects were evident on LPO increase and GSH decrease for the lowest Cr concentration, as well as on CAT and GST decrease for the highest concentration. In contrast, an antagonistic action was observed on DNA integrity loss for both Cr concentrations. The current results are relevant in assessing the interactions of PAHs and metals and contribute to a better knowledge about oxidative stress and mechanisms of genotoxicity in fish.
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PMID:Oxidative stress and genotoxic effects in gill and kidney of Anguilla anguilla L. exposed to chromium with or without pre-exposure to beta-naphthoflavone. 1678 84

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

Active bio-monitoring in terms of biomarkers was attempted using Crassostrea gigas larvae produced in the laboratory and transplanted using special containers to two sites at the entrance (A) and inner part (P) of the harbour of Arcachon (French Atlantic Coast). The larvae were kept in the medium for 48 h. Their physiological status and their biomarker levels : acetylcholinesterase AChE, catalase CAT and glutathione S-transferase GST activities were determined together with metallothionein MT and Thiobarbituric Acid Reactive Substances TBARS concentrations. Copper and PAH (polycyclic aromatic hydrocarbon) concentrations were determined in the exposed larvae and in the sediments collected under the containers. Cadmium, lead and zinc could be also analyzed in the sediments. Toxicity tests demonstrate that the larvae are in better physiological conditions in A compared to P. Larvae transplanted in the inner harbour (P) present relatively high GST activity (869.1+/-39.3 nmol min(-1)mg protein(-1)), TBARS (2.74+/-0.19 nmol mg protein(-1)), compared to those exposed at the harbour entrance (A). Copper measured in the sediments (65+/-1 mg kg(-1) d.w.) collected under the cages at P is higher than at A. Larvae placed in A present higher total PAH concentrations compared to the inner part. The data tend to reveal a lower copper and higher PAH contamination in A than in P. Therefore larvae, developing in the natural medium, show different responses according to their immersion sites. These responses, obtained within 48 h, may be related to the chemical contamination of the environment and may be used for seawater quality assessment in future studies.
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PMID:Marine water quality assessment using transplanted oyster larvae. 1685 46


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