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)

For 25 mutagens in Drosophila the ratio was determined between the induction of sex-linked recessive lethals (SLRL) and the induction of ring-X loss in male adults. For small monofunctional alkylating agents this ratio increases with decreasing s-value from 1.8 for methyl methanesulfonate (MMS) to 27 for ethylnitrosourea (ENU). For multifunctional cross-linking agents, however, the ratio varies within relatively narrow limits, ranging from 0.15 for cisplatin to 0.07 for tris-(1-aziridinyl)phosphineoxide (TEPA), while for most agents the ratio is around 0.12. The number of reactive groups seems to be of minor importance for compounds with more than one functionality as bi- and tri-functional agents show similar ratios. The systemic difference in the ratios between mono- and multi-functional agents suggests that different mechanisms are involved in the induction of SLRLs and ring-X loss. For ethyleneimine (EI) and ethyleneoxide (EO) low ratios of 0.32 and 0.60 respectively were observed which do not correlate with their s-values. An alternative chromosome-breaking mechanism may be responsible for this deviation, possibly alkylation of the phosphate backbone of DNA, followed by an intramolecular displacement of one of the deoxyribose groups by the beta-amino or the beta-hydroxy group. It is felt that the considerable difference between the ratios for monofunctional and multifunctional agents may be of prognostic value and can be used to obtain information on the mechanisms of mutagens with 'unknown' action, provided that structural features are taken into account. Hexamethylphosphoramide (HMPA), hexamethylmelamine (HEMEL), tetramethylurea (TMU) and dimethylpropyleneurea (DMPU) all show SLRL: ring-X loss ratios that match those of multifunctional agents, 0.08, 0.12, 0.08, and 0.16, respectively. The ratios for the pyrrolizidine alkaloids monocrotalin and seniciphilline, 0.053 and 0.24 respectively, also correspond with this group of mutagens. The low ratios for formaldehyde, 2-chloro-acetaldehyde and 2-chloroethyl methanesulfonate, 0.30, 0.052 and 0.36 respectively, are indicative that cross-linking may attribute considerably to their mutagenic action in Drosophila. On the other hand, not all mutagens containing 2 reactive groups act as cross-linking agents. The ratio for 1,2-dibromoethane, 2.7, indicates that it may act as a monofunctional agent. This is in accordance with the proposed activation mechanism by glutathione S-transferase, producing a monofunctional half-mustard derivative (Rannug, 1980; van Bladeren et al., 1981).
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PMID:The ratio of induced recessive lethals to ring-X loss has prognostic value in terms of functionality of chemical mutagens in Drosophila melanogaster. 245 28

Periportal and perivenous hepatocytes were isolated by the digitonin-collagenase perfusion technique. The activity of the cytosolic glutathione S-transferase was higher in perivenous cells, but the cytosolic glutathione reductase and the microsomal glutathione S-transferase activities were evenly distributed. In contrast, both the Se-dependent and the microsomal Se-independent glutathione peroxidase activity and the glucose-6-phosphate dehydrogenase activity was much lower in perivenous hepatocytes, suggesting that these cells have a lowered detoxification capacity, which may contribute to their greater susceptibility to damage by xenobiotics. The mechanism of the ethanol-induced GSH depletion in vivo was studied by incubating conventionally isolated hepatocytes. In the absence of glutathione precursors, ethanol (80 mM) did not influence the GSH content, despite accumulation of acetaldehyde (10-100 MicroM). L-Methionine or L-cysteine stimulated GSH replenishment to in vivo rates. Ethanol oxidation resulted in acetaldehyde accumulation, but did not inhibit GSH replenishment from L-methionine and even stimulated that from L-cysteine. This seems to exclude conjugation of GSH with acetaldehyde as a mechanism by which ethanol suppresses GSH levels in vivo.
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PMID:Glutathione metabolism in isolated rat hepatocytes: acinar heterogeneity of detoxifying enzymes and effects of ethanol. 342 86

The modification potentials of ethyl alcohol (EA) and acetaldehyde (AA) on development of immunohistochemical glutathione S-transferase (placental type)-positive (GST-P+) liver cell foci were examined in an in vivo short-term assay system. Rats were given a single intraperitoneal injection of diethylnitrosamine (DEN) and then various concentrations of EA (20, 10, 5%) or AA (5, 2.5%) in their drinking water from week 2 till termination in week 6. All rats were subjected to two-thirds partial hepatectomy in week 3. Animals given EA (20% and 10%) or AA showed significant decrease in liver and body weight. However, only EA caused significant dose-related inhibition of development of areas of foci (mm2/cm2), but AA had no effect on their development.
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PMID:Modification potentials of ethyl alcohol and acetaldehyde on development of preneoplastic glutathione S-transferase P-form-positive liver cell foci initiated by diethylnitrosamine in the rat. 369 54

The class-3 aldehyde dehydrogenase that is overexpressed (> 100-fold) in human breast adenocarcinoma MCF-7/0 cells made resistant (> 30-fold as judged by LC90s) to oxazaphosphorines, such as mafosfamide, by growing them in the presence of polycyclic aromatic hydrocarbons, e.g., methylcholanthrene (3 microM for 5 days), was isolated and characterized. Its physical and catalytic properties were identical to those of the prototypical human stomach mucosa cytosolic class-3 aldehyde dehydrogenase, type-1 ALDH-3, except that it catalyzed, though not very rapidly, the oxidation of aldophosphamide, whereas the stomach mucosa enzyme essentially did not; hence, it was judged to be a slight variant of the prototypical enzyme. Carcinogens that are not ligands for the Ah receptor, barbiturates known to induce hepatic cytochrome P450s, steroid hormones, an antiestrogen, and oxazaphosphorines did not induce the enzyme or the largely oxazaphosphorine-specific acquired resistance. Whereas methylcholanthrene induced (a) resistance to mafosfamide and (b) class-3 aldehyde dehydrogenase activity, as well as glutathione S-transferase and DT-diaphorase activities, in the estrogen receptor-positive MCF-7/0 cells, it did not do so in two other human breast adenocarcinoma cell lines, MDA-MB-231 and SK-BR-3, each of which is estrogen receptor negative. Expression of the class-3 aldehyde dehydrogenase and the loss of sensitivity to mafosfamide by polycyclic aromatic hydrocarbon-treated MCF-7/0 cells were transient; each returned to essentially basal levels within 15 days when the polycyclic aromatic hydrocarbon was removed from the culture medium. Insensitivity to the oxazaphosphorines on the part of polycyclic aromatic hydrocarbon-treated MCF-7/0 cells was not observed when exposure to mafosfamide (30 min) was in the presence of benzaldehyde or octanal, each a relatively good substrate for cytosolic class-3 aldehyde dehydrogenases, whereas it was retained when exposure to mafosfamide was in the presence of acetaldehyde, a relatively poor substrate for these enzymes. These observations demonstrate that ligands for the Ah receptor can induce a transient, largely oxazaphosphorine-specific, acquired cellular resistance, and they are consistent with the notion that elevated levels of a cytosolic class-3 aldehyde dehydrogenase nearly identical to the prototypical type-1 class-3 aldehyde dehydrogenase expressed by human stomach mucosa account for the Ah receptor ligand-induced oxazaphosphorine-specific acquired resistance, most probably by catalyzing the detoxification of aldophosphamide.
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PMID:Identification of a methylcholanthrene-induced aldehyde dehydrogenase in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. 817 25

The modifying action of experimentally induced chronic liver injury on diethylnitrosamine (DEN) hepatocarcinogenesis was investigated using a minimal treatment protocol. A single dose of DEN (15 mg/kg b.w.) was administered as a carcinogen to 1-day-old Sprague-Dawley rats. From 3 weeks of age rats received repeated intraperitoneal injections of carbon tetrachloride (CCl4), or 10% ethanol or 5% acetaldehyde in the drinking water for 9 weeks. Combinations of CCl4 and ethanol or acetaldehyde were also tested. Morphology, immunohistochemistry for glutathione S-transferase-placental form, and incidence and quantity of preneoplastic lesions of the livers were studied. The chronic CCl4 administration produced complete or incomplete liver cirrhosis and exerted a strong promoting effect on the development of neoplastic nodules. Ethanol alone revealed no cirrhogenous or tumor-promoting effect, but enhanced both actions of CCl4. Acetaldehyde increased only the cirrhogenous effect of CCl4.
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PMID:Effects of carbon tetrachloride, ethanol and acetaldehyde on diethylnitrosamine-induced hepatocarcinogenesis in rats. 833 Feb 98

Previous experiments with hepatocytes isolated from ethanol-treated rats showed that alcohol potentiates the toxic action of 1,2-dibromoethane (DBE) by inhibiting its metabolism via glutathione-S-transferase. The aim of this study was to investigate whether acetaldehyde, the main product of ethanol metabolism, may be responsible for such inactivation. By pretreatment with 4-methylpyrazole, an inhibitor of acetaldehyde formation, the ethanol inactivation of glutathione transferase was actually prevented. As a consequence of this protective action, 4-methylpyrazole also prevented the high basal lipid peroxidation and the potentiated DBE toxicity observed in hepatocytes from ethanol-dosed animals. Finally, the inactivation of glutathione-S-transferase by concentrations of acetaldehyde likely to occur in the ethanol-intoxicated animal was confirmed in an in vitro model by direct aldehyde addition to hepatocyte suspensions.
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PMID:Acetaldehyde involvement in ethanol-induced potentiation of rat hepatocyte damage due to the carcinogen 1,2-dibromoethane. 867 12

Formaldehyde, acetaldehyde, and acrolein are well-known upper respiratory tract irritants and occur simultaneously as pollutants in many indoor and outdoor environments. The upper respiratory tract, and especially the nose, is the prime target for inhaled aldehydes. To study possible additive or interactive effects on the nasal epithelium we carried out 1- and 3-day inhalation studies (6 hr/day) with formaldehyde (1.0, 3.2, and 6.4 ppm), acetaldehyde (750 and 1500 ppm), acrolein (0.25, 0.67, and 1.40 ppm), or mixtures of these aldehydes, using male Wistar rats and exposure concentrations varying from clearly nontoxic to toxic. The (mixtures of) aldehydes were studied for histopathological and biochemical changes in the respiratory and olfactory epithelium of the nose. In addition, cell proliferation was determined by incorporation of bromodeoxyuridine and proliferating cell nuclear antigen expression. Effects were primarily observed after 3 days of exposure. Histopathological changes and cell proliferation of the nasal epithelium induced by mixtures of the three aldehydes appeared to be more severe and more extensive in both the respiratory and the olfactory part of the nose than those observed after exposure to the individual aldehydes at comparable exposure levels. As far as nasal histopathological changes and cell proliferation are concerned neither dose addition nor potentiating interactions occurred at no-toxic-effect levels, except for a possible potentiating effect of acetaldehyde at noneffect levels. The results did not indicate a major role for aldehyde dehydrogenases in the biotransformation of the aldehydes studied. Activities of glutathione S-transferase and glutathione reductase after 3 days of exposure to acrolein, alone or in combination with formaldehyde and acetaldehyde, were depressed whereas the glutathione peroxidase activity was elevated. No decrease of nonprotein sulphydryl levels were observed. These findings suggest that, for no-toxic-effect levels, combined exposure to these aldehydes with the same target organ (nose) and exerting the same type of adverse effect (nasal cytotoxicity), but partly with different target sites (different regions of the nasal mucosa), is not associated with a greater hazard than that associated with exposure to the individual chemicals.
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PMID:Changes in the nasal epithelium of rats exposed by inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein. 874 18

Induced-acetaldehyde toxic effects on gluatathione [GSH] metabolism and sulfhydryl (SH) groups in liver and in brain of female albino rats with reference to age was studied. The total -SH groups were decreased whereas the specific activities of glutathione-S-transferase [GST] and glutathione peroxidase [GPo] were increased in acetaldehyde treated rats. However, the specific activity levels of glutathione reductase [GR] and gamma-glutamylcysteine synthetase [gamma-GCS] were decreased. In general, acetaldehyde induced changes in the specific activities of the enzymes that increase with increasing age.
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PMID:Age-related metabolic effects of acetaldehyde on rats with reference to detoxification enzymes and sulfhydryl groups. 898 6

Histological effects of ethanol on the kidney were published in our previous report. In the present paper, results of the following measurement will be reported: contents of ethanol and related substances in the urine, both free and bound types, collected during the periods from 30 minutes to 11 hours after ethanol administration to rats, and ACE, alpha-GST, LPO, 25(OH)-D3, 1 alpha-25(OH)2-D3, 24, 25(OH)2-D3 in the serum of rats which had ethanol every day for a month. These will be reported together with histological observation of the kidney excised immediately after the blood sample was collected. The measurement of free and bound types ethanol, acetaldehyde, acetone and methanol in the urine was made up to 11 hours after administration of 4 g/kg b.w./day, p.o. and its results showed the highest contents at 9 hours after the administration. Bound type acetic acid showed the high contents at both 90 minutes and 9 hours after the administration. In 11 hours free type ethanol and acetaldehyde recovered their pre-administration value but as to the bound type only acetic acid recovered it. In the serum of the rats which were ethanol 4 g/kg b.w./day, oral administrated for a mouth, ACE showed significantly high value and 1 alpha, 25(OH)2-D3 and 24, 25(OH)2-D3 showed significantly low value relative to the control. Also alpha-GST showed a low value. In the kidney of the same rats the following changes were observed: swelling of glomerulus, thickening of basement membrane of glomerulus, PAS positive deposits in glomerulus, proliferation of mesangial cell, proliferation of juxtaglomenular cell, dilation of tubular lumen, swelling of tubular epithelial cell, its falling, hyaline droplet in tubular epithelial cell, cell infiltration to interstitial tissue, and basophilic tubule. There was not only difference between findings in the control and those in the liver and the brain of the rats which showed changes above-mentioned. As described above, changes were seen in the renal tissue caused by ethanol administration and in this connection changes in indices related to renal function were observed, too. Furthermore, urinary ethanol and related substances, not only free type but also bound type, that went through the kidney were observed for a long period time. The bound type, in particular, was observed for longer duration and hence effects of ethanol on the kidney were surely assumed. Presently longer term experiments are proceeding and other indices connected with renal functions are being studied.
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PMID:[Effect of long-term ethanol administration (2). Free type and bound type ethanol and related substances contents of the urine from ethanol administrated rats, indices in the serum, and renal tissues]. 910 39

Free radicals have previously been shown to kill the immature stages of the trematode, Schistosoma mansoni but their effect on newly excysted juvenile (NEJ) flukes of Fasciola hepatica has not been established. Using acetaldehyde and xanthine oxidase to chemically generate reactive oxygen intermediates (ROI), up to 61% of NEJ were killed but only when exposed to high levels of ROI. At low concentrations of acetaldehyde and xanthine oxidase as sources of reactive oxygen intermediates, only 6-29% of NEJ were killed compared with 70-92% of schistosomula. Incubation with lipopolysaccharide (LPS)-stimulated rat peritoneal lavage cells (PLCs) killed only 7-15% of NEJ whereas 78-87% of schistosomula were killed under the same conditions by a mechanism dependent on the production of reactive nitrogen intermediates. Relative to immature and adult parasites, NEJ expressed 2.5-20-fold lower levels of superoxide dismutase and glutathione S-transferase but no catalase activity was detected. Incubation of NEJ with inhibitors of peroxidases and glutathione metabolism increased the mean killing of NEJ by LPS-stimulated rat PLCs to 40-75%. These results demonstrate that, in comparison to schistosomula of S. mansoni, NEJ of F. hepatica are relatively resistant to killing by free radicals and this resistance could, in part, be due to the activity of oxidant scavenger enzymes of NEJ.
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PMID:Juvenile Fasciola hepatica are resistant to killing in vitro by free radicals compared with larvae of Schistosoma mansoni. 1084 8


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