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

---

Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant melanoma tumors are inherently resistant to anticancer drugs, yet the mechanism of this resistance is not understood. B16 melanoma, a spontaneous tumor which arose in the C57BL/6 mouse; BL6 melanoma, a highly invasive variant; and Mel-ab melanocytes, isolated from C57BL/6 mouse skin, were examined for intracellular glutathione (GSH) content. GSH was higher in BL6 and B16 cells than in Mel-ab cells, with the highest concentration in BL6 cells. Since GSH is thought to be involved in the resistance of many cells, including melanoma, to cytotoxic drugs, we determined whether intracellular GSH content was altered during transformation of Mel-ab cells. After transfection with pHO6T1 plasmid DNA, containing an activated c-H-ras oncogene flanked by transcriptional enhancers, 1.3% of successfully transfected Mel-ab melanocytes formed distinct colonies in soft agar, compared to 0.2% of cells transfected with control pHO6 plasmid without H-ras. Approximately 53% of the pHO6T1-transfected colonies isolated from soft agar grew in 5% CO2 in the absence of phorbol-12-myristate-13-acetate, a requirement for the extended growth of Mel-ab cells. Cells transfected with control pHO6 plasmid and non-transfected Mel-ab cells did not survive under these conditions. All of the isolated pHO6T1 transfected cells formed tumors when inoculated into C57BL/6 mice. Transformed cells had higher GSH content than non-transfected Mel-ab cells, whether expressed on a cellular or cell volume basis. Although the amount of oxidized glutathione was greater in the tumorigenic cells, this could not account for the overall increase in GSH. Neither glutathione S-transferase nor gamma-glutamyl transpeptidase activities were increased in the H-ras-transfected cells. Northern blot analysis confirmed H-ras-specific RNA in pHO6T1-transformed cells.
...
PMID:Induction of glutathione content in murine melanocytes after transformation with c-H-ras oncogene. 171 78

Perfusion of the bovine eye with a buffer solution containing t-butyl hydroperoxide and the glutathione reductase inhibitor nitrofurantoin caused significant decreases in reduced glutathione level in ciliary body and iris. The result was interpreted to suggest that the organic hydroperoxide was decomposed by the glutathione peroxidase-reductase system. The glutathione reductase reaction requires NADPH. Since the level of NADPH is maintained by the hexose monophosphate shunt in many tissues, we investigated whether this is also the case with bovine uveal tissues. CO2 formation from [1-14C]glucose but not from [6-14C]glucose was markedly stimulated by t-butyl hydroperoxide and was inhibited by the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea, thus supporting the importance of the hexose monophosphate shunt for hydroperoxide decomposition through the glutathione peroxidase-reductase system. The peroxidase-reductase activity was found both in non-pigmented and pigmented ciliary epithelial cells in culture. Purification studies isolated two forms of glutathione reductase [GR I (140 kDa) with subunit Mr of 70 kDa and GR II (greater than 670 kDa) with subunit Mr of 45 kDa] and a novel glutathione peroxidase (112 kDa with subunit Mr of 29 kDa). The peroxidase is active both with H2O2 and organic hydroperoxides, does not contain selenium and shows no glutathione S-transferase activity.
...
PMID:Glutathione-dependent detoxification of peroxide in bovine ciliary body. 237 73

Recent evidence supports the concept that Adriamycin cytotoxicity may be mediated by drug semiquinone free radical and oxyradical generation. We tested this hypothesis further by exposing drug-sensitive (WT) and 500-fold Adriamycin-resistant MCF-7 human breast tumor cells (ADRR) to exogenous superoxide- and hydrogen peroxide-generating systems and subsequently monitored cell proliferation as a measure of cytotoxicity. The ADRR tumor cells tolerated a 4-fold greater exposure than sensitive cells to superoxide generated by the xanthine/xanthine oxidase system. Likewise, exposure to hydrogen peroxide produced by the action of glucose oxidase on glucose revealed a 4-fold diminished susceptibility of the drug-resistant cells to this reduced form of oxygen. Similar results were obtained by the direct application of hydrogen peroxide to cells. For both cell lines, cytotoxicity was dependent upon the magnitude and the duration of reactive oxygen exposure. When WT and ADRR cells were cultured under hyperoxia (95% O2:5% CO2), in order to stimulate the intracellular production of oxyradicals, proliferation was inhibited to a greater extent in the drug-sensitive cell line. Additionally, hyperoxia potentiated the cytotoxicity of Adriamycin to both sensitive and drug-resistant cells, but the effect depended upon the concentration of the drug. Under hyperoxic conditions, Adriamycin caused oxygen radical-dependent cytotoxicity to the WT tumor cells at clinically relevant drug concentrations as low as 2 to 3 nM. With ADRR tumor cells, hyperoxia increased the cytotoxicity of Adriamycin at concentrations above 5 microM. Paradoxically, both the WT and the ADRR tumor cells were equally susceptible to the cytotoxic effects of gamma irradiation. It is known that the Adriamycin-resistant MCF-7 cells greatly overexpress glutathione peroxidase and glutathione transferase activities; however, other biochemical defenses against reactive drug intermediates and oxygen radicals have been reported to be similar in the two cell lines. We have reexamined those observations in this report. The resistance of ADRR breast tumor cells to Adriamycin appears to be associated with a developed tolerance to superoxide, most likely because of a twofold increase in superoxide dismutase activity, and a decreased susceptibility to hydrogen peroxide, most likely because of 12-fold augmented selenium-dependent glutathione peroxidase activity. Acting in concert, these two enzymes would decrease the formation of hydroxyl radical from reduced molecular oxygen intermediates.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Differential oxygen radical susceptibility of adriamycin-sensitive and -resistant MCF-7 human breast tumor cells. 253 95

The amount of urea synthesized in intact guinea pig hepatocytes in 60 min ([urea]t=60), was determined at 37 degrees C in Krebs-Henseleit buffer plus (in mM) 10 NH4Cl, 5 lactate, and 10 ornithine in 5% CO2-95% O2. The concentrations of sulfonamide carbonic anhydrase (CA) inhibitors required to reduce the rate of urea synthesis by 50% (I50) were (in mM): 0.07 ethoxzolamide, 0.5 methazolamide, 0.7 acetazolamide, and 5.0 p-aminomethylbenzenesulfonamide. At 37 degrees C acetazolamide and ethoxzolamide reduced citrulline synthesis by intact mitochondria in medium containing (in mM) 50 3-(N-morpholino)propanesulfonic acid, 35 KCl, 5 KH2PO4, 2 adenosine triphosphate, 10 ornithine, 10 NH4Cl, 1 [ethylene-bis(oxyethylenenitrile)]tetraacetic acid, 1 MgCl2, 20 pyruvate, and 25 KHCO3 (pH 7.4) in 5% CO2-95% O2; the inhibition by ethoxzolamide was not decreased greater than 50%; 25% inhibition was achieved by 0.65 microM ethoxzolamide. Inhibition constant (Ki) values for CA activity of disrupted mitochondria at 37 degrees C were 0.03 microM ethoxzolamide and 0.16 microM acetazolamide, and for disrupted hepatocytes were 150 microM ethoxzolamide and 50 microM acetazolamide. p-Aminomethylaminosulfonamide-affinity column purification yields one band of 29,000 mol wt for CA V purified from disrupted mitochondria; homogenized whole-liver supernatant yields an additional band of 20,000 mol wt (at greater than 100 times the concentration of CA V), which has some glutathione S-transferase activity. It is concluded that this 20,000-mol wt protein modifies the potency of ethoxzolamide in the liver cytosol.
...
PMID:Inhibition of mitochondrial carbonic anhydrase and ureagenesis: a discrepancy examined. 312 80

Acrylonitrile caused thiobarbituric acid-positive reactants time- and concentration-dependently in isolated hepatocytes. This effect was markedly enhanced by gassing of the medium with 95% oxygen-5% CO2 gas mixture. Glycidonitrile, an acrylonitrile metabolite, proved more potent in this respect than the parent acrylonitrile or its end metabolite, cyanide anion. The latter decreased greatly the viability of isolated liver cells but caused thiobarbituric acid-positive reactants only in the presence of diethylmaleate. Acrylonitrile caused also a decrease in the concentration of nonprotein sulfhydryl groups but the oxidation of glutathione (GSH) to GSSG (oxidized glutathione) was not the major mechanism. This might indicate the consumption of GSH in the glutathione S-transferase catalyzed reactions. In contrast to cyanide anion-induced effects acrylonitrile did not affect markedly the viability of hepatocytes.
...
PMID:Consequences of acrylonitrile metabolism in rat hepatocytes: effects on lipid peroxidation and viability of the cells. 313 12

The elimination and metabolism of [14-C]-tetrachloroethylene (Tetra) was studied in female rats and mice after the oral administration of 800 mg/kg [14-C]-Tetra. Elimination of unchanged Tetra was the main pathway of elimination in both species and amounted to 91.2% of the dose in rats and 85.1% in mice. [14-C]-Carbon dioxide (CO2) was found to be a trace metabolite of [14-C]-Tetra. Only a small part of the applied dose was transformed to urinary (rats = 2.3%, mice = 7.1%) and fecal (rats = 2.0%, mice = 0.5%) metabolites. The urinary metabolites were separated and quantified by high performance liquid chromatography (HPLC) and identified by gas liquid chromatography/mass spectrometry (GC/MS). The following metabolites could be identified: oxalic acid (8.0% of urinary radioactivity in rats, 2.9% in mice), dichloroacetic acid (5.1%, 4.4%), trichloroacetic acid (54.0%, 57.8%), N-trichloroacetyl-aminoethanol (5.4%, 5.7%), trichloroethanol, free and conjugated (8.7%, 8.0%), S-1,2,2-trichlorovinyl-N-acetylcysteine (N-acetyl TCVC) (1.6%, 0.5%), and another conjugate of trichloroacetic acid (1.8%, 1.3%). The structures of the identified metabolites indicate two different pathways operative in Tetra biotransformation: cytochrome P-450-mediated epoxidation forming reactive metabolites in the liver and conjugation of Tetra with glutathione (GSH) catalyzed by glutathione transferase(s). The formation of reactive intermediates by renal processing of the glutathione conjugates may provide a molecular mechanism for the nephrotoxicity and nephrocarcinogenicity of Tetra in male rats.
...
PMID:Identification of S-1,2,2-trichlorovinyl-N-acetylcysteine as a urinary metabolite of tetrachloroethylene: bioactivation through glutathione conjugation as a possible explanation of its nephrocarcinogenicity. 327 76

We examined the maintenance of functional and morphological integrity of precision-cut rat liver slices cultured in various incubation systems and conditions for 72 h. Slices were incubated (37 degrees C) for 6, 24, 48, and 72 h in supplemented Williams E medium in 6-well plastic culture plates on a gyratory shaking platform (WPCS) or in a rotating organ culture system (ROCS) using 5% CO2--95% air (WPCS/air or ROCS/air) or 5% CO2--70% O2--25% N2 (WPCS/O2 or ROCS/O2). Biochemical and functional parameters of slices maintained in WPCS/air or WPCS/O2 were almost totally inhibited after 24 h, in keeping with the extensive and diffuse coalescing coagulative necrosis typical of post-ischemic injury affecting almost all the slice surface after 48 h. As compared to freshly isolated slices, slices maintained in ROCS/air for 72 h showed stable ATP and GSH content, increased protein synthesis, and a slight steady decrease in GST activity, while ATP and GST activity remained stable and protein synthesis and GSH content increased in slices incubated in ROCS/O2 for 72 h. The extent of coagulative necrosis was markedly lower in longitudinal sections from slices incubated for 72 h in ROCS/O2 than in ROCS/air. Transversal sections from slices kept in ROCS/air for 72 h showed a thick central band of necrotic cells edged by two peripheral layers of viable hepatocytes, whereas most of the slice was composed of viable hepatocytes lined by two thin layers of necrotic cells after 72 h in ROCS/O2. ROCS/O2 emerged as the system best preserving the histological and functional integrity of rat liver slices in long-term culture.
...
PMID:Morphological and functional integrity of precision-cut rat liver slices in rotating organ culture and multiwell plate culture: effects of oxygen tension. 968 91

DCP has been utilized as a soil fumigant for more than 45 yr for the control for parasitic plant nematodes. Injected into soil before planting of crops, the instability of DCP in soil and water and its volatility dictate the principal route of human exposure that may occur, inhalation. Extensive data have been accumulated on the toxicity and metabolism of DCP. DCP is moderately toxic via oral or inhalation exposure, is irritating to the skin and eyes, and has potential to produce skin sensitization. It is rapidly and extensively metabolized. It has a half-life in the blood of rats and humans of only 3-7 min and < 10 min, respectively. Rats and mice excrete approximately 80% of even relatively high oral dosages within 24 hr, primarily as breakdown products of a glutathione conjugate or as carbon dioxide. These products reflect the primary routes of metabolism of DCP, via GSH-conjugative and hydrolytic pathways. An additional pathway based upon the epoxidation of DCP has also been proposed, but this does not appear to occur to any toxicologically significant degree in the presence of normally occurring GSTs. Direct evidence of the latter pathway is only been obtained at dosages of DCP in excess of the reported LD50. Humans also appear to rapidly metabolize DCP and excrete its metabolites. Subchronic toxicity studies of relatively pure DCP in rats and mice via oral or inhalation routes have resulted in portal-of-entry tissue effects that reflect the irritant properties of this chemical to nasal and gastric mucosa. At higher exposure levels in mice, however, toxicity was also identified in a remote tissue, the urinary bladder. Toxicity in dogs ingesting DCP was limited to the formation of a regenerative hypochromic, microcytic anemia. No teratological or reproductive effects were observed in rats or rabbits inhaling DCP vapors. Nonneoplastic changes from chronic dosing of DCP were generally similar to those observed in subchronic studies. Somewhat variable responses, however, have been observed for neoplastic effects, depending on the DCP formulation, route, and species used. Inhalation of a recent formulation increased the benign tumor incidence in the lungs of male mice (only) while ingestion of similar test material by rats and mice resulted in a low incidence of benign liver tumors in rats (only). In contrast, an older formulation containing Epi as a stabilizing agent administered to rats and mice via bolus oral dosing induced a number of malignant or benign tumors: in the forestomach and liver in rats and the forestomach, lung, and urinary bladder in mice. An equally complicated database has accumulated for DCP in vitro and in vivo genotoxicity testing. Genotoxicity has been reported in in vitro assays; however, confounding factors such as low-purity formulations, use of a genotoxic stabilizer, or generation of reactive impurities during attempts to purify test material have complicated interpretation. DCP appears to lack direct DNA reactivity, and a general trend toward decreasing activity with increasing complexity of the assay system and the presence of GST is evident. The weight-of-evidence evaluation of the genotoxicity data base suggests a lack of genotoxicity in vivo. Clearly definable treatment-related effects of DCP suggesting a plausible nongenotoxic mechanism of tumorigenic action, for example, enhanced cell proliferation, have not been in evidence in target tissues of treated animals. Thus, the specific mode of tumorigenesis of DCP in test animals remains to be elucidated but appears to involve a non-DNA-reactive mechanism. In conclusion, DCP-based soil fumigants have maintained an important role in agricultural despite the structural similarity of DCP to known genotoxic carcinogens and its own activity in in vitro genotoxicity assays. This role results from a combination of its use on soils before the planting of crops, its limited environmental half-life, rapid metabolism by animals via GSH conjugation and catabolism to CO2, lack of genotoxicity in in vivo assays, and an extensive toxicological database in animals, including several oncogenicity bioassays. These data, when combined with occupational and environmental exposure information, have provided a scientifically sound basis for the continued safe use of DCP-containing products.
...
PMID:Mammalian toxicity of 1,3-dichloropropene. 1288 26

Deoxynivalenol (DON) and nivalenol (NIV) are toxic Fusarium secondary trichothecene metabolites that often co-occur regularly in cereal grains. These compounds were compared for their toxicity towards C57BL/6 mice on several parameters including alteration in plasma biochemistry, immune system reactivity and hepatic drug metabolism capacity. Mice received individual or combined oral doses of each toxin: 0.071 or 0.355 mg/kg of body weight, administrated three days a week for 4 weeks. Food consumption was altered by the single administration of 0.355 mg/kg of NIV, although no noticeable change of body and organ weights or liver protein contents was detected. NIV administration did cause also significant changes in total CO2 and uric acid concentrations in plasma. Individual toxin exposures led to increases in plasma IgA without no detectable change in the ex vivo production of cytokine by splenocytes. The liver ethoxyresorufin O-deealkylase, pentoxyresorufin O-depenthylase and glutathione S-transferase activities were increased in concert with cytochrome P4501a and P4502b subfamily expression. Administration of combinations of DON and NIV resulted in responses similar to that observed using individual doses of each toxin. However, depending on the ratio of toxin doses and biochemical parameters, some responses could be also additive (plasma IgA and hepatic DCNB conjugation) or synergistic (plasma uric acid).
...
PMID:Individual and combined effects of low oral doses of deoxynivalenol and nivalenol in mice. 1637 17

An ecophysiological experiment was conducted to examine the biochemical effects of acidified seawater containing elevated concentration of CO(2) (C(CO2) 0.08, 0.20, 0.50 and 1.00%) on the copepod Centropages tenuiremis. AchE, ATPase, SOD, GPx, GST, GSH level and GSH/GSSG ratio of the copepod were analyzed. The results showed that elevated C(CO2) and the duration of culture time significantly influenced several biochemical indices in C. tenuiremis (ATPase, GPx, GST, GSH and SOD). Furthermore, the principal component analysis results indicated that 72.32% of the overall variance was explained by the first three principal components (GPx, SOD and GSH). Changes in GPx and GSH levels may play a significant role in the antioxidant defense of copepods against seawater acidification. The long-term response of copepods to seawater acidification and the synergistic effects of acidification with other environmental factors, such as temperature, salinity and trace metal need further investigation.
...
PMID:Biochemical responses of the copepod Centropages tenuiremis to CO(2)-driven acidified seawater. 2217 5


1 2 Next >>

---