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)

Studies were performed to determine the effects of chronic hypoxia on enzymes that catalyze various detoxication reactions. Rats were exposed to room air or 10.5% O2 for 10 days, and microsomes and postmicrosomal supernatants were isolated from liver. Detoxication enzyme activities were measured by radiochemical and spectrophotometric assays, and immunoreactive protein amounts were measured by Western blot analysis. Total cytochrome P450, as measured by the CO-difference spectrum, and activities of superoxide dismutase (EC 1.15.1.1), epoxide hydrolase (EC 4.2.1.63), catalase (EC 1.11.1.6), glutathione disulfide reductase (EC 1.6.4.2), and glutathione (GSH) S-transferase (EC 2.5.1.18) were not affected by this extent of hypoxia. In contrast, 10 days of hypoxia decreased activities or immunoreactivities (% of aerobic) of GSH peroxidase (EC 1.11.1.9) (54%), cytochrome P450EtOH2 (42%), CYP3A1 (53%), sulfotransferase (EC 2.8.2.1) (77%) and UDP-glucuronosyltransferase (EC 2.4.1.17) (65%). Activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), an important enzyme in NADPH production was also decreased to 56% of the aerobic value, but Western blot analysis showed that the amount of protein reactive with antibodies to glucose-6-phosphate dehydrogenase was not affected by hypoxia. Thus, hypoxia may decrease activity of enzymes by regulatory mechanisms even though the amount of immuno-detectable enzyme is unchanged. Liver cells isolated from rats exposed to hypoxia also gave lower GSH synthetic rates than cells from normoxic rats. This result, together with the effect of hypoxia on glucose-6-phosphate dehydrogenase, indicates that the GSH supply for GSH-dependent detoxication reactions may be limited due to chronic hypoxia. To test directly whether chronic hypoxia increased sensitivity to a compound normally detoxified by a GSH-dependent reaction, sensitivity to tert-butyl hydroperoxide (t-BuOOH) of hepatocytes from rats exposed to in vivo hypoxia was compared to that from normoxic rats. The results showed that the cells from the hypoxic rats were much more sensitive to injury. Taken together, these results suggest that decreases in amounts and/or activities of detoxication enzymes during chronic hypoxia may result in increased susceptibility of cells to chemical injury.
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PMID:Effect of chronic hypoxia on detoxication enzymes in rat liver. 161 Apr 6

The metabolism of testosterone and benzo(a)pyrene (BaP) which is mediated by diverse enzymes was determined in cryopreserved rat liver parenchymal cells and compared with that found in freshly isolated cells. In addition, the activities of single xenobiotic-metabolizing enzymes were measured by using specific substrates. The cytochrome P450 (P450)-mediated total metabolic conversion of testosterone was reduced to 55% in cryopreserved cells. The metabolite profile, i.e. the formation of single metabolites compared with total metabolic conversion, was however unchanged when compared with freshly isolated cells. A concomitant reduction in the activities of the involved P450 isoenzymes can therefore be postulated. The amount of detected phase I-metabolites of BaP was unaffected by the cryopreservation method. The formation of phase II-metabolites and total metabolic conversion of BaP in cryopreserved cells was however reduced to about 50-60%. The reduced glutathione S-transferase and more obviously phenol sulfotransferase activities measured in cryopreserved cells, may explain the impaired conjugation of BaP. The ratio between phase I- and phase II-metabolites was thus changed by cryopreservation. Density separation on Percoll yielded cryopreserved cells with a viability and metabolic capacity not measurably different from freshly isolated cells. To this extent, cryopreserved, Percoll-purified liver parenchymal cells are a useful in vitro system for drug metabolism studies. However due to the extensive loss in cell number during this procedure (recovery = 22% of freshly isolated cells) the application of this system is limited.
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PMID:Characterization of cryopreserved rat liver parenchymal cells by metabolism of diagnostic substrates and activities of related enzymes. 164 45

The effect of prolonged exposure to buthionine sulfoximine (BSO) on rat hepatic Phase I and Phase II drug-metabolizing enzymes has been examined. Exposure to 30 mM BSO in drinking water for 7 days induced hepatic microsomal UDP-glucuronosyltransferase activity (detergent-activated) toward p-nitrophenol (250%), 1-naphthol (210%), morphine (130%) and testosterone (140%), but not estrone. Glucuronosyltransferase activities were also induced after exposure for as short as 3 and as long as 13 days. When rats were returned to unsupplemented drinking water for 1 day prior to sacrifice following 6 days on 30 mM BSO, comparable induction to that seen after 7 consecutive days on the BSO solution was observed despite liver glutathione concentration having rebounded to 127% of control. Daily ingestion of BSO was similar (1 mmol/rat/day) for all periods of 30 mM BSO-drinking water exposure, with a body weight-adjusted dose range of 3.2-6.3 mmol/kg/day. An analogous inductive response caused by drinking 30 mM BSO for 3 days was elicited for p-nitrophenol and morphine glucuronidation by 6 mmol/kg doses of BSO given as single daily intraperitoneal or intragastric injections for 3 days. Intraperitoneal, intragastric and all BSO-drinking water exposures also significantly induced (130-195%) cytosolic glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Significant increases in UDP-glucuronosyltransferase and glutathione S-transferase activities were also observed following 3 days of exposure to BSO in the drinking water at a concentration as low as 5 mM. Cytosolic p-nitrophenol sulfotransferase activity, with one minor exception, was not enhanced by any BSO treatment regimen. Alterations in transferase activities were not accompanied by any major changes in either overall cytochrome P-450 concentration or oxidative reactions selective for two isozymes. Thus, in addition to its well-documented glutathione-depleting property, BSO also selectively induces several Phase II drug-metabolizing enzymes, an effect to be considered in studies employing extended BSO treatment.
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PMID:Induction of rat UDP-glucuronosyltransferase and glutathione S-transferase activities by L-buthionine-S,R-sulfoximine without induction of cytochrome P-450. 212 59

Variations in the total capacity of the rat ovary to metabolize xenobiotics during different phases of the estrous cycle were studied. The level of the conjugating enzymes, phenol UDP-glucuronosyltransferase (pUDPGT; EC 2.4.1.17), phenol sulfotransferase (pST; EC 2.8.2.1) and glutathione transferases (EC 2.5.1.18) was determined in the ovary and compared with the corresponding hepatic activities. In addition, catalase (EC 1.11.1.6) and NAD(P)H: quinone oxidoreductase (EC 1.6.99.2) two other detoxifying enzymes, were assayed. In order to study the hormonal influences on detoxifying enzymes, mature rats were characterized with respect to their stage in the estrous cycle. Immature rats were treated with pregnant mare's serum gonadotropin (PMSG) for 2 or 3 days to enrich the ovaries in preovulatory follicles or corpora lutea, respectively. The present study demonstrates that ovarian pUDPGT and pST activities are increased 936% and 175%, respectively, in ovaries enriched in corpora lutea compared to ovaries from untreated immature rats. Increases in these activities in mature rats during the metestrous stage of the estrous cycle compared to the proestrous stage were also noted. In the liver pUDPGT activity is increased significantly (1.6-fold) in immature rats with ovaries enriched in preovulatory follicles compared to untreated rats. Both ovarian pST and pUDPGT activities increased in mature rats treated with PMSG ("hyperstimulated"), while in the liver only pST was increased by such treatment. Ovarian glutathione transferase activity proved not to be dependent on the hormonal fluctuations associated with the estrous cycle. However, in the liver of mature rats treated with PMSG, this activity increased 2-fold compared to the untreated immature rats. The catalase activity found in the ovarian mitochondrial fraction was approx. 10-fold higher than in the cytosolic fraction, independent of the hormonal status. Moreover, we found a significant 1.4-fold increase in peroxisomal catalase activity in the mitochondrial fraction of immature rats treated with PMSG, both when enriched in preovulatory follicles and in corpora lutea. In the liver cytosolic catalase activity decreased several-fold in immature rats following PMSG treatment. We did not find any variations in ovarian NAD(P)H: quinone oxidoreductase activity during the estrous cycle, whereas in the liver this activity decreased in the luteal phase, as it did in mature rats treated with PMSG. From this study and earlier investigations in our laboratory, we conclude that cyclic variations due to hormones of the estrous cycle of the major 7,12-dimethylbenz(a)anthracene (DMBA)-metabolizing phase I enzymes in the ovary are not accompanied by increases in the activities of the corresponding phase II enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormonal influences of detoxication in the rat ovary on enzymes in comparison with the liver. 787 55

Rat liver parenchymal cells were isolated by EDTA perfusion and were subsequently purified by Percoll centrifugation. The freshly isolated liver cells had a mean viability of 95% as judged by trypan blue exclusion. Isolated liver parenchymal cells were then stored at 0 degrees C for up to 1 wk in University of Wisconsin solution (UW). During this hypothermic preservation, the viability was only slightly reduced to 92% after 1 d and to 85% after 3 d at 0 degrees C. Thereafter, the viability decreased rapidly. After cold storage for up to 3 d, it was possible to use the parenchymal liver cells either in short-term suspension or in cell culture. The attachment efficiency in cell culture was the same for freshly isolated liver cells (84%) and after 2 d cold preservation (81%). The cytochrome P450 content and the enzyme activities of soluble epoxide hydrolase, UDP-glucuronosyl transferase, phenol sulfotransferase, and glutathione S-transferase were not significantly different between freshly isolated cells and cells after 3 d of hypothermic preservation. Furthermore, freshly isolated and intact liver cells stored for 3 d were used in the cell-mediated Salmonella mutagenicity test as a metabolizing system. Both fresh and stored liver parenchymal cells metabolized benzo(a)pyrene,2-aminoanthracene, and cyclophosphamide to their ultimate mutagens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Viability, attachment efficiency, and xenobiotic metabolizing enzyme activities are well maintained in EDTA isolated rat liver parenchymal cells after hypothermic preservation for up to 3 days in University of Wisconsin solution. 852 13

Human bronchial epithelial cells (BEC), a primary defense against inhaled materials, are the progenitor cells for bronchogenic carcinomas and have important metabolic capabilities. We used reverse transcriptase-polymerase chain reaction (RT-PCR) to identify xenobiotic metabolism enzymes expressed in primary BEC and alveolar macrophages (AM) of non-smoking volunteers. Cytochromes P450 (CYP) 1A1, 1B1, 2B7, 2E1, and 4B1 and microsomal epoxide hydrolase (mEH) were expressed in BEC but not AM. CYP2F1 was expressed in BEC, but it was expressed at barely detectable levels or not at all in AM. NADPH oxidoreductase (NADPH OR), microsomal glutathione transferase (GST 12), glutathione transferase mu, phenol sulfotransferase (PST), thermolabile phenol sulfotransferase (TL PST), and the clara cell-specific gene, CC10 were expressed in both BEC and AM. CYP3A4 and glucuronosyl transferases-1 and 2 were not expressed in either BEC or AM. In contrast to primary BEC, of the genes evaluated, the immortalized human bronchial epithelial cell line BEP2D constitutively expressed only CYP1A1, CYP2E1, NADPH OR, glucuronosyl transferase 1, GST 12, GST mu, PST, TL PST, and CC10. The loss of xenobiotic metabolism enzyme gene expression in the BEP2D cell line may result from either reduced exposure to inducing agents, or loss of differentiative characteristics in culture. It is clear from the data comparing BEC and AM that there are important intertissue differences in expression of xenobiotic metabolism enzymes.
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PMID:Xenobiotic metabolism enzyme gene expression in human bronchial epithelial and alveolar macrophage cells. 884 77

The filamentous fungus Cunninghamella elegans has the ability to metabolize xenobiotics, including polycyclic aromatic hydrocarbons and pharmaceutical drugs, by both phase I and II biotransformations. Cytosolic and microsomal fractions were assayed for activities of cytochrome P450 monooxygenase, aryl sulfotransferase, glutathione S-transferase, UDP-glucurono-syltransferase, UDP-glucosyltransferase, and N-acetyltransferase. The cytosolic preparations contained activities of an aryl sulfotransferase (15.0 nmol min-1 mg-1), UDP-glucosyltransferase (0.27 nmol min-1 mg-1) and glutathione S-transferase (20.8 nmol min-1 mg-1). In contrast, the microsomal preparations contained cytochrome P450 monooxygenase activities for aromatic hydroxylation (0.15 nmol min-1 mg-1) and N-demethylation (0.17 nmol min-1 mg-1) of cyclobenzaprine. UDP-glucuronosyltransferase activity was detected in both the cytosol (0.09 nmol min-1 mg-1) and the microsomes (0.13 nmol min-1 mg-1). N-Acetyltransferase was not detected. The results from these experiments provide enzymatic mechanism data to support earlier studies and further indicate that C. elegans has a broad physiological versatility in the metabolism of xenobiotics.
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PMID:Phase I and phase II enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. 902 50

Phenol sulfotransferase (PST, EC 2.8.2.1) and glutathione-S-transferase (GST, EC 2.5.1.18), the phase II biotransformation enzymes inactivate many exo- and endogenous compounds. The effect of PST substrates (catecholamines, simple phenols, selected phenolic drugs) and PST products (phenolic sulfates) on GST activity was investigated to identify possible interactions between sulfation and glutathione conjugation in the brain. Two soluble forms of PST and two forms of GST were isolated from monkey (Rhesus macacus) brain cortex. Catecholamines, hypertensive and hypotensive drugs which are sulfated by monkey brain PSTs slightly inhibit the activity of brain GSTs. The greatest inhibitory effect was observed with neurotoxic compounds such as 6-OHDA and manganese. The commonly used analgesic drugs inhibit both GST forms. These enzymes are also inhibited by phenacetin, the precursor of paracetamol, and prototype salicylates such as sodium salicylate and acetylsalicylic acid. The effect of simple phenols and their sulfated metabolites on GST activity varies. The obtained results point to a possible interaction between sulfation and glutathione conjugation in vivo since many physiologically, therapeutically and toxicologically active compounds which are sulfated by brain phenol sulfotransferases may be bound by brain glutathione-S-transferases. These compounds may lose their activity (on being bound to GST) and expose the brain to the toxic electrophiles (by decreasing GST activity).
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PMID:Biotransformation in monkey brain: coupling of sulfation to glutathione conjugation. 936 30

The dose responses for several effects of low-level limited exposures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126, 0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by 32P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsulfotransferase activity, a key enzyme in the metabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced no increase in cell proliferation, whereas the high exposure resulted in a marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed the placental form of glutathione S-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the low and mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantial incidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposure group, only one adenoma occurred at 36 weeks in 17 rats, while in the low exposure group, no liver tumor occurred in 23 rats. Thus, these findings document nonlinearities for some of the effects of AAF, with supralinear effects at the high exposure for cell proliferation and induction of HAF, and a no-observed-effect level for induction of promotable liver neoplasms at the lowest cumulative exposure of 0.126 mmol/kg, in spite of the formation of DNA adducts. We conclude that the effects of this DNA-reactive hepatocarcinogen leading to initiation exhibit nonlinearities and possible thresholds.
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PMID:Nonlinearities in 2-acetylaminofluorene exposure responses for genotoxic and epigenetic effects leading to initiation of carcinogenesis in rat liver. 984 22

It has become clear that several polymorphisms of human drug-metabolizing enzymes influence an individual's susceptibility for chemical carcinogenesis. This review gives an overview on relevant polymorphisms of four families of drug-metabolizing enzymes. Rapid acetylators (with respect to N-acetyltransferase NAT2) were shown to have an increased risk of colon cancer, but a decreased risk of bladder cancer. In addition an association between a NAT1 variant allele (NAT*10, due to mutations in the polyadenylation site causing approximately two fold higher activity) and colorectal cancer among NAT2 rapid acetylators was observed, suggesting a possible interaction between NAT1 and NAT2. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) are polymorphic due to large deletions in the structural gene. Meta-analysis of 12 case-control studies demonstrated a significant association between the homozygous deletion of GSTM1 (GSTM1-0) and lung cancer (odds ratio: 1.41; 95% CI: 1.23-1.61). Combination of GSTM1-0 with two allelic variants of cytochrome P4501A1 (CYP1A1), CYP1A1 m2/m2 and CYP1A1 Val/Val further increases the risk for lung cancer. Indirect mechanisms by which deletion of GSTM1 increases risk for lung cancer may include GSTM1-0 associated decreased expression of GST M3 and increased activity of CYP1A1 and 1A2. Combination of GST M1-0 and NAT2 slow acetylation was associated with markedly increased risk for lung cancer (odds ratio: 7.8; 95% CI: 1.4-78.7). In addition GSTM1-0 is clearly associated with bladder cancer and possibly also with colorectal, hepatocellular, gastric, esophageal (interaction with CYP1A1), head and neck as well as cutaneous cancer. In individuals with the GSTT1-0 genotype more chromosomal aberrations and sister chromatid exchanges (SCEs) were observed after exposure to 1,3-butadiene or various haloalkanes or haloalkenes. Evidence for an association between GSTT1-0 and myelodysplastic syndrome and acute lymphoblastic leukemia has been presented. A polymorphic site of GSTP1 (valine to isoleucine at codon 104) decreases activity to several carcinogenic diol epoxides and was associated with testicular, bladder and lung cancer. Microsomal expoxide hydrolase (mEH) is polymorphic due to amino acid variation at residues 113 and 139. Polymorphic variants of mEH were associated with hepatocellular cancer (His-113 allele), ovarian cancer (Tyr-113 allele) and chronic obstructive pulmonary disease (His-113 allele). Three human sulfotransferases (STs) are regulated by genetic polymorphisms (hDHEAST, hM-PST, TS PST). Since a large number of environmental mutagens are activated by STs an association with human cancer risk might be expected.
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PMID:Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. 1002 93


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