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 study investigated the relationship between lipid peroxidation and enzyme inactivation in rat hepatic microsomes and whether prior inactivation of aldehyde dehydrogenase (ALDH) exacerbated inactivation of other enzymes. In microsomes incubated with 2.5 microM iron as ferric sulfate and 50 microM ascorbate, ALDH, glucose-6-phosphatase (G6Pase) and cytochrome P450 (Cyt-P450) levels decreased rapidly and concurrently with increased levels of thiobarbituric acid-reactive substances. Microsomal glutathione S-transferase and nicotinamide adenine dinucleotide phosphate-cytochrome c reductase were little affected during 1 hr of incubation. Addition of reduced glutathione partially protected and N,N'-diphenyl-p-phenylenediamine and butylated hydroxytoluene completely protected microsomes against inactivation of ALDH, G6Pase and Cyt-P450, as well as lipid peroxidation induced by iron and ascorbate. ALDH was more susceptible than G6Pase to inactivation by iron and ascorbate, and was thus an excellent marker for oxidative stress. Inhibition of ALDH by cyanamide injection of rats exacerbated the inactivation of G6Pase in microsomes incubated with 0.1 mM, but not 25 microM 4-hydroxynonenal (4-HN). 4-HN did not stimulate lipid peroxidation. Thus, 4-HN may play a minor role in microsomal enzyme inactivation. In contrast, lipid peroxyl radicals play an important role in microsomal enzyme inactivation, as evidenced by the prevention of both lipid peroxidation and enzyme inactivation by chain-breaking antioxidants.
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PMID:Glutathione and antioxidants protect microsomes against lipid peroxidation and enzyme inactivation. 160 2

Effects of dietary iron deficiency on inductions of putative preneoplastic lesions and oxidative alterations in the livers of rats by a choline-deficient L-amino acid defined (CDAA) diet were examined. Male Fischer 344 rats, 4 weeks old, were used with a total experimental period of 16 weeks, consisting of 4-week pretreatment and 12-week treatment periods (periods A and B respectively). During period A, a choline-supplemented L-amino acid defined (CSAA) or an iron-deficient CSAA diet was administered, and the CDAA or an iron-deficient CDAA diet was fed in period B. Formation of 8-hydroxydeoxyguanosine (8OHdG), a DNA adduct generated by activated oxygen species, in DNA and lipid peroxidation in liver cell membranes were sequentially determined after the beginning of period B. At the end of the experiment, development of gamma-glutamyltransferase (GGT) and glutathione S-transferase placental form (GSTP) positive liver lesions were quantitatively analysed. In the animals fed the CDAA diet, formation of 8OHdG and lipid peroxidation increased with time, and GGT and GSTP positive liver lesions developed. Formation of 8OHdG, lipid peroxidation and the numbers of induced enzyme-altered liver lesions were all reduced in rats fed the iron-deficient CSAA diet in period A and/or the iron-deficient CDAA diet in period B. The present results indicate that iron plays an important role in induction of preneoplastic liver lesions in rats caused by exposure to the CDAA diet possibly in connection with its known catalytic role in generation of highly reactive activated oxygen species.
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PMID:Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet. 163 91

This study determined whether acetaminophen (ACAP)-induced glutathione depletion was associated with liver lipid peroxide formation, or the concentrations of liver S-adenosylmethionine and S-adenosylhomocysteine in mice fed diets with L-methionine below or at the requirement level (0.25 or 0.5%) for 7 wk. Iron dextran (281 mg/kg body wt) or saline was administered for 2 d before measurement of lipid peroxide formation. Chronic dietary ACAP (0.5%) in mice fed 0.25% methionine caused a failure to maintain body weight even though food intake was similar to intake by all other treatment groups. Liver GSH (measured as nonprotein sulfhydryl concentration) and cysteine concentrations were depleted by ACAP and by ACAP plus iron. Liver lipid peroxide formation was increased by iron but was not altered additionally by ACAP ingestion. Liver glutathione peroxidase activity was increased by methionine in controls, whereas glutathione S-transferase activity was increased by ACAP ingestion in mice fed 0.5% methionine compared with controls. Liver S-adenosylmethionine and nuclear 5-methyldeoxycytidine concentrations were not affected by dietary ACAP or methionine. Liver S-adenosylhomocysteine levels were lower in mice fed ACAP and 0.25% methionine compared with mice fed ACAP and 0.5% methionine. In conclusion, chronic ACAP did not increase the susceptibility of mice to liver lipid peroxidation or alter the availability of methyl groups for methylation reactions.
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PMID:Prolonged acetaminophen ingestion by mice fed a methionine-limited diet does not affect iron-induced liver lipid peroxidation or S-adenosylmethionine. 164 Feb 69

Inducibility of oxidative stress in rat liver in vivo by menadione-associated redox cycling activation under redox enzyme modulating conditions was examined by monitoring hepatocyte injury and 8-hydroxydeoxyguanosine (8-OHdG) levels of liver DNA. In addition, the treatment-associated liver tumor initiating activity was assessed in terms of development of gamma-glutamyl-transpeptidase (GGT)- and glutathione S-transferase placental form (GST-P)-positive foci and hyperplastic nodules. With or without following menadione treatment (50 mg/kg, i.g.), redox enzyme modulations of increased cytochrome P450 reductase activity induced by phenobarbital (PB)-Na (100 mg/kg, i.p. for 5 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.) and depletion of glutathione by phorone (200 mg/kg, i.p.), with or without further supplement of iron EDTA-Na-Fe(III) (70 mg/kg, i.p.), caused both substantial hepatocyte necrosis and 8-OHdG production in Fischer 344 male rats. Subsequent feeding with a 0.05% PB diet for 64 weeks resulted in slightly increased development of GGT-positive foci but not GST-P positive lesions or hyperplastic nodules, suggesting a lack of tumor-initiating activity of the oxidative DNA damage associated with redox enzyme modulations with or without menadione.
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PMID:Induction of 8-hydroxydeoxyguanosine but not initiation of carcinogenesis by redox enzyme modulations with or without menadione in rat liver. 170 52

The level of quinone oxidoreductases (microsomal and cytosolic DT-diaphorase, NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase), superoxide dismutase and glutathione-related enzymatic activities in diethylstilbestrol (DES)-induced carcinogenesis in kidney from Syrian golden hamsters are presented. Animals that exhibited two different stages of DES-induced carcinogenesis in kidney--pre- and neoplastic lesions and tumorous lesions (after 6 and 8 months of continuous exposure to DES respectively)--were studied in comparison to kidneys from control animals. A dramatic decrease in microsomal and cytosolic DT-diaphorase activities (13.6 and 37.8% of controls), as well as in glutathione disulphide reductase (39.5%), and less marked in superoxide dismutase (45.6%), NADH cytochrome b5 reductase (61.9%) glutathione transferase (GST) towards 1-chloro-2,4-dinitrobenzene (CDNB) (66.2%) and glutathione peroxidase (GSH-Px) (80%) activities, were observed in kidneys with pre- and neoplastic lesions. NADPH-cytochrome P450 reductase and GST activity towards 4-hydroxy-2,3-trans-nonenal (4-HNE) showed no statistically significant variation at this stage of carcinogenesis. In kidney from animals with tumorous lesions, all the enzymatic activities mentioned above decreased, except for superoxide dismutase, which was increased to 186% of the control activity. GST activity towards 4-HNE again showed no statistically significant variation. These results suggest that if one-electron reduction of diethylstilbestrol-4',4''-quinone (DESQ) occurs, it may play a very important role in the development of DES carcinogenesis (pre- and neoplastic lesions), since at this stage of carcinogenesis the primary defense mechanisms against the oxygen free radicals generated in this way, i.e. SOD activity, is reduced to less than a half of control values. Both cytosolic and microsomal DT-diaphorase activities are unable at this stage of carcinogenesis to promote effectively the two-electron reduction of DESQ, which would avoid the initial formation of superoxide anion. The consequences of these decreases may be an increased steady-state concentration of superoxide anion and hydrogen peroxide, which in the presence of iron might lead to lipid peroxidation. GST activity towards 4-HNE could be responsible for the possible higher steady-state concentration of this lipid peroxidation product during DES treatment. The induction of DT-diaphorase and its protective role in the prevention of the development of pre- and neoplastic lesions in kidney from Syrian golden hamster during DES treatment is also discussed.
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PMID:The levels of quinone reductases, superoxide dismutase and glutathione-related enzymatic activities in diethylstilbestrol-induced carcinogenesis in the kidney of male Syrian golden hamsters. 211 5

After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Anthracyclines. 222 2

The glutathione-glutathione peroxidase system is an important defense against oxidative stress. The ability of this system to protect against iron-catalyzed microsomal production of hydroxyl radicals [oxidation of 4-methylmercapto-2-oxo-butyrate (KMBA)] and lipid peroxidation was evaluated. When rat liver cytosol was added to microsomes, strong inhibition against KMBA oxidation was observed. No protection was found when the cytosol was boiled or dialyzed. In the latter case, the addition of 0.5 mM glutathione restored almost complete protection, whereas in the former case protection could be restored by the addition of both glutathione and glutathione peroxidase. Cysteine could not replace glutathione, nor could glutathione S-transferase replace glutathione peroxidase. The glutathione-glutathione peroxidase system was also very effective in decreasing production of hydroxyl radicals stimulated by the addition of menadione or paraquat to microsomes. In the absence of cytosol, the addition of glutathione plus glutathione peroxidase was also effective; however, 5 mM glutathione was necessary to protect against KMBA oxidation. The effective concentration of glutathione required for protection was lowered when glutathione reductase was added to the system, to regenerate reduced glutathione. These results indicate that low concentrations of glutathione in conjunction with glutathione peroxidase plus reductase can be very effective in preventing microsomal formation of hydroxyl radicals catalyzed by iron and other toxic compounds. Microsomal lipid peroxidation was decreased 40% by glutathione alone, and this decrease was potentiated in the presence of glutathione reductase. In contrast to KMBA oxidation, the combination of glutathione plus glutathione peroxidase was not any more effective than glutathione alone in preventing lipid peroxidation. The differences in sensitivities of microsomal lipid peroxidation and KMBA oxidation to glutathione peroxidase suggest that these two processes can be distinguished from each other, and that free H2O2 and hydroxyl radicals are involved in KMBA oxidation, but not lipid peroxidation.
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PMID:Prevention of microsomal production of hydroxyl radicals, but not lipid peroxidation, by the glutathione-glutathione peroxidase system. 301 60

Interleukin-1 (IL-1) activity and the acute phase response, as measured by plasma CRP and iron, were used to determine if the standard disease modifying antirheumatic drugs (DMARDs), gold, chloroquine and D-penicillamine had a common profile of activity in the adjuvant arthritic (AA) rat. All drugs were tested at a dose which significantly reduced noninjected paw swelling in AA rats. Inhibition of paw edema ranged from 37% for D-penicillamine (100 mg/kg) to 69% for auranofin (10 mg/kg). Two week medication of AA rats with gold sodium thiomalate (GST, 10 mg/kg, i.m.) or auranofin (10 mg/kg, p.o.) resulted in a significant decrease in splenic IL-1 activity, as measured in the standard lymphocyte activating factor (LAF) assay. The acute phase response, often associated with elevated IL-1 activity, was also significantly reduced following treatment of AA rats with 10 mg/kg of GST or auranofin (oral gold). Inhibition of the acute phase response by gold was determined by a significant reduction of plasma CRP levels (56-71% reduction) and enhancement of plasma iron levels (27-52% enhancement). In contrast to the effect of GST and auranofin on IL-1, CRP and iron, treatment with chloroquine (20, 30 and 35 mg/kg) and D-penicillamine (55 and 100 mg/kg) failed to reduce the acute phase response (as measured by plasma CRP and iron) or alter LAF activity from AA rat spleen cell supernatants. Based on its ability to reduce LAF activity in spleen cell supernatants and reduce the acute phase response, it is possible that the activity of gold in the AA rat may in part be due to its ability to inhibit IL-1 production in vivo. The inability of chloroquine and D-penicillamine to alter LAF activity and the acute phase response in AA rats does not preclude their possession of an immunoregulatory mechanism of action, but it does indicate that their mechanism of action in the AA rat probably differs from that of GST and auranofin.
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PMID:Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs. 314 30

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces atrophy, morphological changes, impaired spermatogenesis, and epididymal lesions in testis of experimental animals. The effects of TCDD administration to male rats on various parameters in the testes were examined. 2. Nine days after TCDD administration, significant decreases in body and testes weights occurred. However, the testes weight as a percent of body weight was higher in treated than control animals. 3. An increase in lipid peroxidation (content of thiobarbituric acid reactive substances) occurred in conjunction with the decrease in testicular weights. 4. TCDD administration produced a 3-fold increase in protein kinase C activity, small but significant decrease is superoxide dismutase and glutathione peroxidase activities, and no effect on catalase, glutathione reductase or glutathione S-transferase activities in the testes. 5. Nine days after treatment with TCDD, in the testes the iron content of whole tissue and cytosol increased while a decrease in microsomal iron was observed. The copper content of mitochondria and microsomes decreased with a corresponding increase in cytosol copper content. A small increase in the zinc content of whole testes occurred. 6. The data indicate that testicular atrophy due to TCDD may be associated with lipid mobilization and peroxidation.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced alterations in lipid peroxidation, enzymes, and divalent cations in rat testis. 324 26

The human hepatoma cell line Hep 3B, which has the hepatitis B virus genome, shows over 80% decrease of copper/zinc superoxide dismutase activity, over 90% decrease of manganese superoxide dismutase activity, over 70% decrease of catalase activity, absence of glutathione peroxidase and glutathione S-transferase activities, over 270-fold increase of ferritin content and 25-fold increase of total iron compared to normal autopsy liver. These conditions of low antioxidant enzyme activities and iron overload are those which support the accumulation of oxygen free-radicals and DNA damage commonly considered to be carcinogenic mechanisms.
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PMID:Antioxidant systems in tumour cells: the levels of antioxidant enzymes, ferritin, and total iron in a human hepatoma cell line. 350 92


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