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)

Numerous experimental evidence sustains a pathogenic role for oxidative stress in aging. Acute and chronic ethanol metabolism is also known to be associated with oxidative perturbation of cellular oxidant/antioxidant balance. In the present work we investigated the effects of 25 months of ethanol consumption on the antioxidant defense system in different organs of rats, in comparison with normal and aged animals. We show that aged rats underwent a significant perturbation of the antioxidant defense system, as indicated by depletion of reduced glutathione content, increases in oxidized glutathione and free radical-induced urinary luminescence associated with a decrease of glutathione reductase and increase of glutathione transferase activities. These modifications, observed particularly in the liver and brain, were enhanced by long-term alcohol exposure. Our results indicate that increased glutathione transferase activity and decreased glutathione reductase activity, followed by thiol depletion, are important factors sustaining a pathogenic role for oxidative stress in aging and in all situations where age-correlated changes occur. They also reinforce the oxidative potential of toxic compounds, such as ethanol intoxication.
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PMID:Long-term ethanol administration enhances urinary ultraweak luminescence and age-dependent modulation of redox in central and peripheral organs of the rat. 963 2

A rare outbreak of acute hepatic damage in workers exposed to dichloropropanols (DCPs) was reported recently. The purpose of the present study is to examine the effects of DCPs on various organs, the dose dependency and the pathogenetic potential of DCP hepatotoxicity. A single intraperitoneal injection was given to six groups of rats with 0.2 ml of 20% ethanol (control), or 1/8 x, 1/4 x, 1/2 x, 1 x, and 2 x LD50 (0.11 ml/kg) of 1,3-dichloro, 2-propanol (DC2P) diluted in 20% ethanol. After blood samplings, all organs were subjected to histologic examinations with light and electron microscopes. Fresh liver tissues from further 4 control and 4 experimental rats sacrificed 6 hours after the injection of 20% ethanol and 1 x LD50 of DC2P were homogenized and subjected to evaluate lipid peroxidation, glutathione S-transferase activity and reduced glutathione contents in the liver. The rats administered with only ethanol or 1/8 and 1/4 LD50 of DC2P showed no serological or histopathological abnormalities. Marked elevation of serum glutamate pyruvate transaminase (SGPT) with a diffuse massive necrosis of the liver cells were noted in all rats of both the 1 x and 2 x LD50 groups, and irregular zonal necroses were found in 3 of 4 rats injected with 1/2 LD50. There were no serious toxic changes in other organs. Hepatic malondialdehyde level was significantly increased, associated with decreases of liver glutathione S-transferase activity and reduced glutathione content. It was concluded that the serious DC2P-toxicity was mainly found in the livers, dose dependently, and one of the causative mechanisms of this hepatotoxicity might be the lipid peroxidation.
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PMID:Dose-dependent effects of dichloropropanol on liver histology and lipid peroxidation in rats. 981 Jan 44

Hepatocytes entrapped in collagen gel and cultured in serum-free conditions survived longer than cells cultured on plastic (5 days vs. 3 weeks), showed fewer signs of early cell senescence (no increase in c-fos oncoprotein expression), and maintained the expression of differentiated hepatic metabolic functions over a longer period of time. Cells cultured in collagen gels retained their ability to respond to hormones. The insulin-stimulated glycogen synthesis rate remained fairly constant during 18 days in culture (between 5.4 +/- 0.37 and 9 +/- 2.7 nmol glucose/h/microg DNA). Collagen-cultured hepatocytes recovered glycogen stores to levels similar to those found in liver, or in hepatocytes isolated from fed rats. Urea synthesis from ammonia remained stable for more than 2 weeks (average value, 23 +/- 4 nmol urea/h/microg DNA). The rate of albumin synthesis in collagen-entrapped cells was maintained above the day-1 level during 18 days in culture. Cells showed high levels of glutathione (GSH) (1,278 +/- 152 pmol/microg DNA). Biotransformation activities CYP4501A1, CYP4502A2, CYP4502B1, and CYP4503A1 remained fairly stable in collagen-cultured hepatocytes. CYP4502E1 and CYP4502C11 decreased but were still measurable after 18 days. After 4 days in culture, GST activity returned to levels observed in isolated hepatocytes. In contrast with plastic cultures, cells responded to CYP450 inducers (methylcholanthrene for CYP4501A1, CYP4501A2, and glutathione-transferase, and ethanol for CYP4502E1) for more than 2 weeks. CYP4501A1, CYP4501A2, and glutathione-transferase A2 (GST A2) induction was preceded by an increase in specific mRNA, while the effects on CYP4502E1 seemed to be at a posttranslational level. Analysis of the expression of relevant hepatic genes by reverse Northern and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that culturing hepatocytes in collagen gels results in a sustained higher expression of key liver transcription factor genes DBP, C/EBP-alpha and -beta, and HNF-1 and -4, as well as specific liver enzyme genes (phosphoenol pyryvate carboxykinase, and carbamoylphosphate-synthetase I).
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PMID:Long-term expression of differentiated functions in hepatocytes cultured in three-dimensional collagen matrix. 1009 8

There are few reports regarding the effects of benzene and ethanol being administered simultaneously. In our experiments with 4 groups (controls, ethanol, benzene and ethanol plus benzene) Wistar male rats were treated with ethanol (20%) for 5 weeks, and then exposed to benzene (0.26 g/kg) for 5 days per week for 3 weeks. We also investigated the effects of benzene on the body weight, organ weight, peripheral hematology and hepatic drug metabolizing enzymes in the ethanol administrated rats. The liver weight increased significantly, but spleen weight decreased significantly in the benzene exposed group. Hematological examination showed a decrease of leukocyte in the two groups of benzene and ethanol plus benzene in comparison with the controls, but an effect promoted by ethanol was not found. Serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) values were not significantly different in the exposure groups when compared with the controls. The contents of microsomal cytochrome P450 in all the exposed groups showed a tendency to increase, but they were not significantly different in comparison with the controls. On the other hand, hepatic glutathione S-transferase activity in the exposed groups increased significantly.
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PMID:[Effect of benzene exposure on hematology and hepatic drug metabolic enzymes in ethanol administrated rats]. 1020 90

The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a powerful mechanism-based competitive inhibitor of the anticancer target enzyme glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor cells in vitro because it does not readily diffuse across cell membranes. We describe an efficient method for indirectly delivering the enzyme inhibitor into murine leukemia L1210 cells via acyl interchange between intracellular glutathione and the cell-permeable prodrug S-(N-p-chlorophenyl-N-hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl-interchange reaction in a cell-free system is 1.84 mM-1 min-1 (100 mM potassium phosphate buffer, 5% ethanol, pH 7.5, 25 degrees C). Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (kapp = 1. 41 +/- 0.03 min-1 (37 degrees C)) and inhibition of cell growth (GI50 = 0.5 +/- 0.1 microM). This represents an improvement in both efficiency and potency over the dialkyl ester prodrug strategy in which the inhibitor is indirectly delivered into tumor cells as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that pi-glutathione transferase catalyzes the acyl-interchange reaction between GSH and the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit greater selective toxicity toward tumor cells that overexpress the transferase.
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PMID:A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides. 1034 34

Airway epithelial surface is the primary target of airborne pollutants. To estimate the distribution of xenobiotic-metabolizing enzymes in the respiratory tract of dogs, epithelia from different airway sites of four animals were analyzed for metabolism of sulfite (sulfite oxidase) and formaldehyde (formaldehyde dehydrogenase and aldehyde dehydrogenase). In addition, glutathione S-transferases were assayed using several model substrates. Enzyme activities were compared with those found in liver parenchyma. The activity of sulfite oxidase was found to be comparable in nose, trachea, and proximal and medium bronchi, but appeared to be lower in lung parenchyma of most animals. In contrast, hepatic sulfite oxidase activity of these animals was substantially higher compared to that in airway epithelia. The activity of glutathione-dependent formaldehyde dehydrogenase (FDH) appeared to be highest in nose and lowest in distal bronchi, lung, and liver parenchyma. The distribution pattern of the glutathione-independent aldehyde dehydrogenase (AldDH) in the respiratory tract was different from that of FDH. Levels of AldDH were about 5- to 10-fold lower than those of FDH, suggesting that AldDH is of minor importance for pulmonary formaldehyde detoxification. With regard to ethanol detoxification by a class I alcohol dehydrogenase (ADH), no measurable enzyme activity could be detected at most respiratory sites contrary to the high activity found in liver parenchyma. Regarding glutathione S-transferases (GSTs), different distributions of enzyme activities were found in the large and small airways when using three substrates. The 1-chloro-2,4-dinitrobenzene (CDNB)-related activities in the cytosolic fraction of the upper (nose, trachea) and lower airways (proximal, medium and distal bronchi) were higher than those in the microsomal fraction. Interestingly, there was no difference between CDNB-related activities in the cytosolic and microsomal fraction of the liver. Highest cytosolic activities were found in the nose, and were comparable to those detected in the liver parenchyma. The cytosolic 1,2-dichloro-4-nitrobenzene (DCNB)-related activities in the nose, proximal bronchi, and lung parenchyma were appeared to be markedly higher than those in trachea and medium and distal bronchi, while the microsomal activities were not detectable at most respiratory sites. In contrast, distinctly higher activities were measured in both fractions of liver tissue. Cytosolic 1, 2-epoxy-3-(p-nitrophenoxy)-propane (EPNP)-related activities were present in upper and lower airways including lung parenchyma at comparable levels, while in liver tissue the mean activities were distinctly lower. No EPNP-related activities were found in the microsomal fractions. In conclusion, most xenobiotic-metabolizing enzymes investigated in this study could be detected in epithelia of various respiratory sites. The most outstanding result revealed higher levels of FDH activity in the nose and downstream to the medium bronchi in comparison to those found in the small airways, lung, and liver tissue. Similarly, the EPNP-related GST exhibited a distinctly higher activity at all respiratory sites compared to the activity in liver tissue, suggesting a different regulation of this enzyme in lung and liver.
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PMID:Xenobiotic-metabolizing enzymes in the canine respiratory tract. 1038 Jan 57

The expression of glutathione (GSH)-dependent enzymes and cytochrome P450 (P450) proteins in freshly isolated proximal tubular cells from human kidney (hPT), and the effect of primary culture on these enzymes, were determined. Freshly isolated hPT cells had relatively high activities of gamma-glutamyltransferase, gamma-glutamylcysteine synthetase, glutathione S-transferase (GST), glutathione disulfide reductase, and GSH peroxidase. Cytochrome P450 4A11 was detected in freshly isolated hPT cells, whereas CYP2E1 was not. Freshly isolated hPT cells also expressed GSTA, GSTP, and GSTT but not GSTM. Primary cultures of hPT cells maintained their epithelial-like nature and diploid status, based on measurements of morphology, cytokeratin expression, and flow cytometric analysis. hPT cells retained GSH-dependent enzyme activities during primary culture, whereas cells that had undergone subsequent passage exhibited a loss of activities of most GSH-dependent enzymes and no longer expressed P450s or GSTs. CYP4A11 expression in primary cultures of hPT cells was significantly increased after treatment for 48 h with either ethanol (50 mM) or dexamethasone (7 nM). GSTA, GSTP, and GSTT contents, although still detectable, were decreased compared with those of freshly isolated hPT cells. Our data show that hPT cells express enzymes involved in xenobiotic disposition, and that they thus provide a model suitable for studies of human renal drug metabolism. Furthermore, primary cultures of hPT cells may afford the opportunity to study factors regulating P450 enzyme expression in human kidney.
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PMID:Expression of glutathione-dependent enzymes and cytochrome P450s in freshly isolated and primary cultures of proximal tubular cells from human kidney. 1077 44

Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), N-acetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.
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PMID:Polymorphism of drug-metabolizing enzymes in relation to individual susceptibility to industrial chemicals. 1081 37

The effect of hydroalcoholic (80% ethanol, 20% water) extract of leaves of Aegle marmelos was examined on carcinogen-metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation, using two doses of dried extract (50 and 100 mg kg(-1) daily for 14 days), in the liver of mice. The modulatory effect of the extract was also examined on extrahepatic organs (lung, kidney and fore-stomach) for effects on the activity of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase. Extract treatment significantly increased the basal levels of acid-soluble sulphydryl (-SH) content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase, DT-diaphorase, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in the liver. Aegle acted as a bifunctional inducer since it induced both phase-I and phase-II enzyme systems. Both doses significantly decreased the activity of lactate dehydrogenase and formation of malondialdehyde in liver, suggesting a role in cytoprotection as well as protection against pro-oxidant-induced membrane damage. Butylated hydroxyanisole (positive control) induced almost all the antioxidative parameters measured in this study. The extract was effective in inducing glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase in lung, glutathione S-transferase, DT-diaphorase and superoxide dismutase in fore-stomach, and DT-diaphorase and superoxide dismutase in lung. These significant changes in the levels of drug-metabolizing enzymes and antioxidative profiles are strongly indicative of the chemopreventive potential of this plant, especially against chemical carcinogenesis.
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PMID:Effect of Aegle marmelos on biotransformation enzyme systems and protection against free-radical-mediated damage in mice. 1100 71

Ethanol, a human toxicant and a solvent in pharmacological research, is known to interfere with biotransformation of xenobiotics. We compared the in vivo and in vitro long-term effects of ethanol exposure on the expression of glutathione S-transferases (GST, EC 2. 5.1.18) in rat liver. Long-term in vivo ethanol treatment to achieve blood ethanol levels ranging between 10-50 mM was by liquid diet feeding. For in vitro experiments, rat hepatocytes co-cultured with rat liver epithelial cells were exposed to 17 and 68 mM ethanol for up to 10 days. Two weeks of liquid diet ethanol treatment increased total GST activity. Both Mu and Alpha classes and in particular the A1 and A2 subunits and the amount of their corresponding mRNAs were increased. Total GST activity was also increased in co-cultures after exposure to 68 mM ethanol for 10 days. However, the Mu class subunits M1 and M2 and the corresponding mRNAs were increased, rather than the Alpha class subunits. Thus, long-term exposure to ethanol induces hepatic GST both in vivo and in vitro, but different isoenzymes are affected. Consequently, extrapolation of in vitro data on GST expression and regulation to the in vivo situation must be judicious. During xenobiotic metabolism in cell culture, a shift in relative expression and induction of different GST forms may occur, resulting in either an under- or overestimation of effects.
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PMID:Effect of ethanol on the expression of hepatic glutathione S-transferase: an in vivo/in vitro study. 1102 Apr 51


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