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 expression of immunoreactive glutathione S-transferase (GST) was examined in hepatic neoplasms induced in rainbow trout by aflatoxin B1 (AFB) or 1,2-dimethylbenzanthracene (DMBA). Tumors were induced in adult trout by continuous dietary exposure to 8 p.p.b. AFB1 for 12 months or embryo bath exposure to DMBA (5 p.p.m. for 24 h, 3 times with 12 h intervals between exposures). Polyclonal antiserum specific for the two major trout hepatic GST subunits in trout liver was produced by immunizing rabbits with affinity-purified trout GST. Hepatocellular, cholangiolar and mixed neoplasms as well as foci of hepatocellular alteration were examined for GST immunoreactivity by the PAP technique. The majority of lesions were GST-deficient (AFB treated, 67%; DMBA treated, 54%), whereas GST expression was induced in 21% (AFB treated) and 31% (DMBA treated) of altered hepatic foci. The GST-induced foci were consistently small (AFB treated, 0.07 +/- 0.05 mm2; DMBA treated, 0.02 +/- 0.01 mm2) and none had progressed beyond the altered focus stage. The majority of larger advanced lesions (adenomas and carcinomas) were GST deficient (AFB treated, 2.33 +/- 0.35 mm2; DMBA treated, 2.95 +/- 0.59 mm2). These studies demonstrate that induced GST expression occurs in some small populations of hepatocytes, but not in larger advanced stages of malignant progression of aflatoxin- or PAH-induced hepatic neoplasms in rainbow trout.
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PMID:Expression of immunoreactive glutathione S-transferases in hepatic neoplasms induced by aflatoxin B1 or 1,2-dimethylbenzanthracene in rainbow trout (Oncorhynchus mykiss). 170 71

A series of environmentally occurring nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) including those containing nitro-groups oriented coplanarly to the aromatic rings, such as 1- and 3-nitrobenzo[a]pyrene (1- and 3-NBAP), 6-nitrochrysene, and 1- and 4-nitropyrene, and those with a molecular orientation of the nitro-groups perpendicular to the aromatic moieties, such as 7-nitrobenz[a]anthracene and 6-nitrobenzo[a]pyrene (6-NBAP), were used to study the induction of certain rat hepatic phase II conjugating enzymes. Effects of these two different classes of nitro-PAHs on microsomal UDP-glucuronyltransferase (UDPGT), cytosolic glutathione S-transferases (GSTs) and sulfotransferases (STs) were investigated. After three consecutive daily i.p. injections, 1- and 3-NBAP and 6-nitrochrysene significantly increased the activities of UDPGT and GST, whereas their parent PAHs did not induce UDPGT (and GST activity was also unaltered by benzo[a]pyrene). UDPGT and GST activities were also significantly increased by 1-nitropyrene. In contrast, the sulfotransferases directed to 2-naphthol were not significantly induced by any PAH or nitro-PAH when assayed at either pH 5.5 or 7.5; however, the activities of aryl STs III and IV (pH 5.5) were significantly decreased following treatment with pyrene and two nitro-compounds, 6-NBAP and 7-nitrobenz[a]anthracene, in which the nitro-group is oriented perpendicular to the aromatic moiety. These results indicate that a coplanar orientation of the nitro-group of certain nitrated PAHs facilitates the induction of hepatic phase II enzymes by these compounds in rats, and the comparable induction patterns for P450IA1, UDPGT, and GST provide further evidence supporting the coordinate regulation (through the Ah receptor) of these phase I and phase II activities.
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PMID:Effect of nitro-substitution of environmental polycyclic aromatic hydrocarbons on activities of hepatic phase II enzymes in rats. 251 57

Toxic effects of SO2 and sulfite such as bronchitis and bronchoconstriction have been well documented. SO2 has also been suggested to potentiate carcinogenic effects of PAH. However, the molecular basis of these toxic effects is unclear. We have examined the covalent reaction of SO2 and sulfite with cellular proteinacious and nonproteinaceous sulfhydryl compounds using rat liver, and lung and human lung derived A549 cells. Reactions of sulfite and protein in rat and human lung cells reveals at least three proteins with sulfite-reactive disulfide bonds. Besides fibronectin and serum albumin, which had been reported to contain sulfonated products following exposure to sulfite, we have found one other protein with sulfite-binding capabilities. Since the integrity of disulfide bonds is crucial to the tertiary structure and thus protein function, the disruption of protein structure by sulfitolysis may result in altered cellular activities leading to biochemical lesions. Using carefully controlled conditions, reproducible GSH contents can be found in cultured cells and used as an experimental basis for studying alterations in the GSH and GSSG content of cells. Sulfitolysis of GSSG results in the formation of GSSO3H in A549 cells, and possibly in the lung. GSSO3H can be reduced enzymatically by GSSG reductase. However, the Km of GSSO3H is high compared to that of GSSG, suggesting the existence of a transient concentration of GSSO3H once it is formed. Cysteine S-sulfonate is, however, not reduced by cytosolic extracts in the presence of NADPH and would have to be eliminated from the cell by other means. GSSO3H is a strong competitive inhibitor of GST in rat liver and lung and A549 cells, using 1-chloro-2,4-dinitrobenzene as a substrate. It also inhibits the formation of GSH conjugates of BP 4,5-oxide, anti and syn BPDE, but to a lesser extent. These results suggest that SO2 may affect the detoxification of xenobiotic compounds by inhibiting, via formation of GSSO3H, the enzymatic conjugation of GSH and reactive electrophiles. Since GSH conjugation represents the major pathway of elimination of BP epoxides in the lung, our results offer a possible explanation for the cocarcinogenicity of SO2 with PAHs. These data suggest that the sulfitolysis reaction of sulfite is the common reaction mechanism mediating the underlying biochemical reactions leading to both the toxic and cocarcinogenic properties of SO2. Quantitation of sulfitolysis products and their interaction with cellular processes should provide a coherent scheme relating SO2 and sulfite toxicity among animal species and humans.
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PMID:Covalent reactions in the toxicity of SO2 and sulfite. 376 76

The GSTs of M. edulis provide an easily assayed activity which would be expected to respond to changes in pollution status. The main GST and a related GSH-binding protein have been purified and biochemically characterized. The former protein is most similar to the Pi class while the latter is a catalytically inactive monomer which appears to be related to the Mu class. This enzyme activity has been assessed as a potential indicator of exposure to chemical pollutants in both Cork Harbour and Venice Lagoon (using the closely related species, M. galloprovincialis). Controlled exposure studies with mussels in holding tanks have indicated that the herbicide aldicarb gives a slight but significant increase in GST activity consistent with the inducibility of these enzymes by xenobiotics in this bivalve. At present, we are studying samples which have been deliberately exposed to PAH and PCB compounds. Studies of this type are important in helping to understand the effects and fate of chemical pollutants released into estuarine environments.
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PMID:Drug metabolizing enzymes of mussels as bioindicators of chemical pollution. 767 33

The CYP and GST genetic polymorphisms, controlling metabolism of xenobiotics, are considered to influence an individual's susceptibility to environmental and occupational carcinogens and predisposition to cancer. In the study, the effect of the GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms was investigated in relation to PAH-DNA adduct levels in non-tumourous lung tissue from non-small cell lung cancer (NSCLC) patients living in the industrialized region of Upper Silesia, Poland. The level of adducts among smokers was significantly elevated when compared to non-smokers (P = 0.0005). Adduct levels correlated inversely with age of patients (P = 0.00001). The GSTP1 and CYP2D6 polymorphisms had no influence on DNA adduct levels. There was a significant relationship between high adduct levels and the combined GSTM1 (null)/CYP1A1-Ile/Val genotype in the squamous cell carcinoma group (P = 0.028). An elevated number of adducts was found in patients with the GSTM1 (null)/CYP1Al-Ile/Val genotype compared to the GSTM1 (null)/CYP1A1-Ile/Ile carriers (P = 0.043). A higher frequency of the CYP1A1-Ile/Val and GSTM1 (null)/CYP1A1-Ile/Val genotypes was observed in patients with high adduct levels (P = 0.05 and P = 0.009, respectively). A significant prevalence of the GSTM1(null)/CYP1A1-Ile/Val carriers in the adenocarcinoma group was found (P = 0.003). Thus, our findings imply that the GSTMI and CYP1A1 exon 7 polymorphisms may influence PAH-DNA adduct levels in target tissue from NSCLC patients, especially in the squamous cell carcinoma group. Moreover, individuals carrying the GSTM1(null)/CYP1A1-Ile/Val genotype might exhibit a greater predisposition to a peripheral type of lung cancer.
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PMID:GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms in lung cancer patients from an environmentally polluted region of Poland: correlation with lung DNA adduct levels. 1049 7

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.
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PMID:Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. 1057 54

International scientific publications on the influence of metabolic genotypes on biological indicators of genotoxic risk in environmental or occupational exposure are reviewed. Biomarkers of exposure (substance or its metabolites in biological fluids, urinary mutagenicity, protein and DNA adducts) and of effects (chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (Mn), COMET assay, HPRT mutants) have been evaluated according to different genotypes (or phenotypes) of several activating/detoxifying metabolic activities. In less than half the studies (43 out of 95), the influence of genotype on the examined biological indicator was found, of which four report poorly reliable results (i.e., with scarce biological plausibility, because of the inconsistency of modulated effect with the type of enzymatic activity expressed). As regards urinary metabolites, the excretion of mercapturic acids (MA) is greater in subjects with high GST activity, that of 1-pyrenol and other PAH metabolites turns out to be significantly influenced by genotypes CYP1A1 or GSTM1 null, and that of exposure indicators to aromatic amines (AA) (acetylated and non-acetylated metabolites) is modulated by NAT2. In benzene exposure, preliminary results suggest an increase in urinary t, t-muconic acid (t,t-MA) in subjects with some genotypes. On urinary mutagenicity of PAH-exposed subjects, the effects of genotype GSTM1 null, alone or combined with NAT2 slow are reported. When DNA adduct levels are clearly increased in PAH-exposed group (18 out of 22), 7 out of 18 studies report the influence of GSTM1 null on this biomarker, and of the five studies which also examined genotype CYP1A1, four report the influence of genotype CYP1A1, alone or in combination with GSTM1 null. A total of 25 out of 41 publications (61%) evaluating the influence of metabolic polymorphisms on biomarkers of effect (cytogenetic markers, COMET assay, HPRT mutants) do not record any increase in the indicator due to exposure to the genotoxic agents studied, confirming the scarce sensitivity of these indicators (mainly HPRT mutants, Mn, COMET assay) for assessing environmental or occupational exposure to genotoxic substances. Concluding, in determining urinary metabolites for monitoring exposure to genotoxic substances, there is sufficient evidence that genetically-based metabolic polymorphisms must be taken into account in the future. The unfavourable association for the activating/detoxifying metabolism of PAH is also confirmed as a risk factor due to the formation of PAH-DNA adducts. The clearly protective role played by GSTT1 on DEB (and/or related compound)-induced sister chromatid exchanges (SCEs) should be noted. The modulating effects of genotypes on protein adduct levels in environmental and occupational exposure have not yet been documented, and most studies on the influence of genotype on biological indicators of early genotoxic effects report negative results.
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PMID:Biological indicators of genotoxic risk and metabolic polymorphisms. 1101 45

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.
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PMID:[Biomarkers of gentotoxic risk and metabolic polymorphism]. 1118 84

The inducibility of hepatic cytosolic glutathione S-transferases (GSTs) was examined in brown bullheads, a freshwater fish that is highly susceptible to hepatic neoplasia following exposure to carcinogen-contaminated sediments. Juvenile bullheads were fed a semi-purified antioxidant-free diet supplemented with ethoxyquin (0.5% w/w dissolved in 3% corn oil), a prototypical rodent GST-inducing agent, twice daily for 14 days. Control bullheads received the antioxidant-free diet supplemented with corn oil (3% w/w). A significant increase (1.6-fold, p < or = 0.01) in hepatic cytosolic GST activity toward 1-chloro-2,4-dinitrobenzene (CDNB) was observed in the ethoxyquin-treated bullheads relative to control fish. A trend toward increased GST-NBC activity was observed in the ethoxyquin-treated fish (1.2-fold, p = 0.06), whereas no treatment-related effects were observed on GST activities toward ethacrynic acid (ECA). In contrast, GST activity toward (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide (BPDE) was repressed in affinity-purified cytosolic fractions prepared from ethoxyquin-treated bullheads relative to control bullheads. Silver staining and densitometric analysis of isoelectric-focused, affinity-purified GST proteins revealed increased expression of two basic GST-like isoforms in ethoxyquin-treated fish. In summary, exposure to ethoxyquin increases brown bullhead GST-CDNB catalytic activity and hepatic cationic GST protein expression. However, the increase in overall GST-CDNB activity by ethoxyquin is associated with repression of GST-BPDE activity, suggesting differential effects on hepatic bullhead GST isoforms by ethoxyquin. The potential repression of bullhead GST isoforms that conjugate the carcinogenic metabolites of PAH metabolism under conditions of environmental chemical exposure could be a contributing factor in the sensitivity of bullheads to pollutant-associated neoplasia.
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PMID:Induction of glutathione S-transferase activity and protein expression in brown bullhead (Ameiurus nebulosus) liver by ethoxyquin. 1139 93

Certain chemopreventive agents are thought to work in part via induction of GST expression. We have utilized transgenic cell lines to show that GST expression can protect against DNA alkylation, and in some cases cytotoxicity caused by electrophilic carcinogens conjugated by GSTs (e.g. 4-NQO, B[a]P, DiB[a,l]P, AFB(1), and certain drugs). However, factors governing protection by GST are complex and vary with different agents and end-points. For example, expression of GST alone was sufficient for partial protection against DNA alkylation by 4-NQO, but protection against 4-NQO cytotoxicity was only observed when the ATP-dependent GS-X transport protein MRP1 was also co-expressed. The dynamic competition between activation and detoxification is the focus of current studies in cells that co-express both CYP1A1 and either hGSTP1 or hGSTM1. Expression of hGSTP1 largely blocked B[a]P toxicity induced via the moderate activation by rat or human CYP1A1. With DiB[a,l]P, GSTs gave up to 7-fold protection against toxicity only when activated by human CYP1A1. However, cells with CYP1A1+GST remained at least 20-fold more sensitive to DiB[a,l]P than parent cells lacking either activity, due to strong activation by hCYP1A1. In summary, we have found that protection by GSTs against B[a]P or DiB[a,l]P toxicity is highly variable depending on differences in: (a) the PAH structure; (b) the human vs. rat CYP1A1 expressed; (c) GST isozyme(s) expressed; (d) cellular expression of conjugate transporters; or (e) DNA damage versus cytoxicity end-points.
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PMID:Modeling the metabolic competency of glutathione S-transferases using genetically modified cell lines. 1250 23


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