Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amount of reduced glutathione in transplantable hepatomas and in a primary DEN-induced hepatoma is lower than in normal liver. In all tumors examined, the glutathione decrease is not due to an increase of oxidized glutathione. In this paper the in vitro activities of two enzymes involved in glutathione synthesis, gamma-glutamylcysteine synthetase and glutathione synthetase, are studied in normal adult rat liver, in regenerating rat liver and in highly anaplastic Yoshida AH-130 hepatoma cells. The activity of these enzymes was determined in the postmicrosomal supernatant fraction as nmoles of [U-14C]-glutamate incorporated into product per mg of soluble protein. In Yoshida AH-130 hepatoma, the gamma-glutamylcysteine synthetase and glutathione synthetase activities are lower in respect to normal liver. This is in agreement with the low glutathione content observed in the hepatoma cells. On the other hand, in regenerating liver, there are minimal differences in comparison with normal liver.
 ...
PMID:Glutathione synthesis in normal liver and in Yoshida AH-130 hepatoma. 380 95

We investigated the effects of glutathione-S-transferase (GST) inhibitor treatment on human colon HT29 cell mRNA levels of dihydrodiol dehydrogenase (DDH), glyoxalase I, and gamma-glutamylcysteine synthetase. Time- and concentration-dependent increases in both DDH and gamma-glutamylcysteine synthetase mRNAs resulted from treatment with ethacrynic acid, ethacrynic acid/glutathione conjugate, and T.199 (gamma-glutamyl-S-(benzyl)-cysteinyl-R(-)-phenyl glycine diethyl ester), a selective GST pi inhibitor. In contrast, glutathione analogue GST alpha- and GST mu-selective inhibitors did not induce expression of these genes. Treatment with ethacrynic acid or T.199 had no effect on the mRNA levels of the glutathione-dependent glyoxalase I gene. Pretreatment of cells with buthionine-DL-sulfoximine, a gamma-glutamylcysteine synthetase inhibitor and glutathione depleter, coupled with ethacrynic acid, ethacrynic acid/glutathione conjugate, or T.199 resulted in greater levels of gamma-glutamylcysteine synthetase and DDH induction compared with single treatments. Treatment with buthionine-DL-sulfoximine alone resulted in modest increases in both gamma-glutamylcysteine synthetase and DDH expression. Analyses of DDH induction by both differential Northern hybridization with specific oligonucleotides as probes and reverse transcriptase-polymerase chain reaction amplification of products, followed by diagnostic restriction digestion with endonucleases, showed that ethacrynic acid induced multiple DDH transcripts in HT29 cells and human HepG2 and SKHep1 hepatoma cells. Possible induction mechanisms include the alteration of sulfhydryl status by the electrophilic properties of EA or by elevations of endogenously generated oxidative stress via transient removal of GST pi from the cytosolic GST pool.
 ...
PMID:Modulation of detoxification gene expression in human colon HT29 cells by glutathione-S-transferase inhibitors. 747 89

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells. 757 30

Induction of glutathione S-transferase (GST) Ya gene expression by a variety of chemical agents is mediated by a regulatory element composed of two adjacent AP-1-like binding sites and activated by the Fos/Jun heterodimeric complex (AP-1). We have previously shown that the induction of GST Ya gene expression and of AP-1 binding activity is regulated by intracellular glutathione (GSH) levels. To study the role of reactive oxygen species in the induction of AP-1 activity and GST Ya gene expression and their effect on intracellular GSH levels, we have exposed hepatoma cells to adriamycin and two synthetic quinones, Qcb and Qn, with different capacities to generate oxygen radicals. The kinetics of quinone-mediated generation of hydroxyl radicals were monitored in intact cells by a spin trapping technique and EPR spectral measurements. We find that quinones which can chelate Fe(III) ions, adriamycin and Qcb, are more effective in hydroxyl radical production than the nonchelating quinone Qn. Furthermore, we show that the induction of AP-1 binding activity and GST Ya gene expression by these quinones correlates with their oxygen radical production, adriamycin and Qcb being stronger inducers that Qn. The present study indicates that the AP-1-mediated induction of GST Ya gene expression is part of the response to oxidative stress. A transient increase by 2.5-fold in the intracellular GSH level was observed 30 min after exposure of cells to quinone and was followed by a rapid depletion of GSH. This increase in the GSH level represents an induction of GSH synthesis since it was blocked by buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Role of quinone-mediated generation of hydroxyl radicals in the induction of glutathione S-transferase gene expression. 781 27

The murine aromatic hydrocarbon ([Ah]) gene battery consists of at least six genes that code for two functionalizing (Phase I) enzymes and four non-functionalizing (Phase II) enzymes. These enzymes are induced by compounds such as aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that bind to the cytosolic Ah receptor protein. Studies in rodents indicate that certain enzymes of this battery, namely cytochrome P4501A1 (CYP1A1), UDP-glucuronosyltransferase (UGT1*06) and NAD(P)H: quinone acceptor oxidoreductase (NMO1) are induced by the synthetic antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII). The induction of [Ah] gene battery enzymes and the levels of reduced glutathione (GSH) were examined in mouse Hepa-1c1c7 hepatoma wild-type cells (wt), a CYP1A1 metabolism-deficient mutant (c37) and an Ah receptor nuclear translocation-defective mutant (c4). DHII and TCDD increased the activities of ethoxyresorufin O-deethylase, an indicator of CYP1A1 activity, as well as NMO1, UGT1*06, cytosolic aldehyde dehydrogenase class 3 and glutathione S-transferase form A1 in wt cells, but had little or no induction effect in c37 or c4 cells. DHII and TCDD differed in their effects on GSH levels; while DHII increased GSH levels 3-fold in wt, but not at all in c37 or c4 cells, TCDD had no effect on GSH levels in any cell type. However, GSH levels were enhanced in both wt and c4 cells by tert-butyl hydroquinone (TBHQ). L-Buthionine S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, prevented DHII-induced increases in wt cell GSH. The increase in GSH levels occurred after 8 h, while the induction of enzymes occurred within 4 h. The induction of the higher GSH levels in wt cells by DHII and TBHQ correlated with increases in intracellular levels of the GSH precursor thiol cysteine, as well as with increased activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis. However, TBHQ-mediated GSH increases in c4 cells were accompanied by increased gamma-glutamylcysteine synthetase activity with no change in intracellular cysteine concentration. The results suggest that DHII induction of [Ah] gene battery enzymes requires a functional Ah receptor, but not the functional gene product CYP1A1. Furthermore, metabolism, possibly via CYP1A1, appears to be required for DHII to enhance intracellular levels of cysteine and GCS activity that result in higher GSH levels.
 ...
PMID:Regulation of [Ah] gene battery enzymes and glutathione levels by 5,10-dihydroindeno[1,2-b]indole in mouse hepatoma cell lines. 795 76

The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatoma. Recently, abnormal copper accumulations in Long-Evans Cinnamon rat livers were shown to be genetically linked to the development of hepatitis. Because reduced glutathione and glutathione-related enzymes are known to play important roles in cellular resistance to transition metal toxicity, we determined the levels of reduced glutathione and glutathione-related enzymes in seven different tissues of Long-Evans Cinnamon and control Long-Evans Agouti rats. Of the enzymes examined, only hepatic glutathione peroxidase was markedly decreased in Long-Evans Cinnamon rats. Glutathione peroxidase content in the liver of Long-Evans Cinnamon rats was 39%, 53% and 58% of the control values at 9 (normal stage), 19 (acute hepatitis stage) and 27 (chronic hepatitis stage) wk of age, respectively. Northern-blot analysis revealed that messenger RNA levels of glutathione peroxidase in the livers of Long-Evans Cinnamon rats were about 40% of the control levels. The activity of glutathione S-transferase was slightly decreased in the livers of Long-Evans Cinnamon rats. These data suggest that the liver of the Long-Evans Cinnamon rat is poorly protected against active oxygen species, the production of which is enhanced in the presence of excess copper. Glutathione-reductase activity in the livers of Long-Evans Cinnamon rats increased to 166% and 148% of the control levels at 19 and 27 wk of age, respectively. No significant changes were observed in the activity of gamma-glutamylcysteine synthetase or in the content of total reduced glutathione in the liver of the Long-Evans Cinnamon rat.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Decreased expression of liver glutathione peroxidase in Long-Evans cinnamon mutant rats predisposed to hepatitis and hepatoma. 811 95

We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an alpha, beta-unsaturated carbonyl of 9-deoxy-delta 9,12-13,14-dihydroPGD2 (delta 12-PGJ2), on the cytotoxicity of delta 12-PGJ2. delta 12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The delta 12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by delta 12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of delta 12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the delta 12-PGJ2-induced apoptosis by regulating the accessibility of delta 12-PGJ2 to target proteins containing thiol groups.
 ...
PMID:Intracellular glutathione level modulates the induction of apoptosis by delta 12-prostaglandin J2. 887 36

Expression of the MRP1 gene encoding the GS-X pump and of the gamma-GCSh gene encoding the heavy (catalytic) subunit of the gamma-glutamylcysteine synthetase is frequently elevated in many drug-resistant cell lines and can be co-induced by many cytotoxic agents. However, mechanisms that regulate the expression of these genes remain to be elucidated. We report here that like gamma-GCSh, the expression of MRP1 can be induced in cultured cells treated with pro-oxidants such as tert-butylhydroquinone, 2,3-dimethoxy-1, 4-naphthoquinone, and menadione. Intracellular reactive oxygen intermediate (ROI) levels were increased in hepatoma cells treated with tert-butylhydroquinone for 2 h as measured by flow cytometry using an ROI-specific probe, dihydrorhodamine 123. Elevated GSH levels in stably gamma-GCSh-transfected cell lines down-regulated endogenous MRP1 and gamma-GCSh expression. ROI levels in these transfected cells were lower than those in the untransfected control. In the cell lines in which depleting cellular GSH pools did not affect the expression of the MRP1 and gamma-GCSh genes, only minor increased intracellular levels of ROIs were observed. These results suggest that intracellular ROI levels play an important role in the regulation of MRP1 and gamma-GCSh expression. Our data also suggest that elevated intracellular GSH levels not only facilitate substrate transport by the MRP1/GS-X pump as previously demonstrated, but also suppress MRP1 and gamma-GCSh expression.
 ...
PMID:Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress. 981 7

Time- and dose-dependent increases in the steady-state mRNA levels of the genes encoding the catalytic and regulatory subunits of the enzyme gamma-glutamylcysteine synthetase (GCS) were observed in HepG2 human hepatocarcinoma cells after exposure to pyrrolidine dithiocarbamate (PDTC). PDTC was demonstrated to manifest both antioxidant and pro-oxidant properties in HepG2 cells, as assessed by the decreased fluorescence of the redox-sensitive dye Dihydrorhodamine 123 and by the oxidation of glutathione respectively. Attempts to characterize the signalling pathway from PDTC exposure to increases in the expression of the GCS catalytic and regulatory subunit genes demonstrated that induction by PDTC could be partially blocked by treatment with the thiol agent N-acetylcysteine and by the copper chelator bathocuproine disulphonic acid. These findings suggested that the up-regulation of the two genes resulted from a PDTC-induced pro-oxidant signal, which was partially copper-dependent. In summary, these studies demonstrate that PDTC exposure elicits a cellular response in HepG2 cells, characterized by the induction of the genes encoding the two subunits of the enzyme GCS and increased de novo synthesis of the cellular protectant GSH.
 ...
PMID:Pyrrolidine dithiocarbamate up-regulates the expression of the genes encoding the catalytic and regulatory subunits of gamma-glutamylcysteine synthetase and increases intracellular glutathione levels. 1005 36

Induction of cytochrome P450 2E1 (CYP2E1) by ethanol appears to be one of the central pathways by which ethanol generates a state of oxidative stress. Glutathione (GSH) is critical in preserving the proper cellular redox balance and for its role as a cellular protectant. The goal of the present study was to characterize the GSH homeostasis in human hepatocarcinoma cells (HepG2-E47 cells) that overexpress CYP2E1. Toxicity in the E47 cells was markedly enhanced after GSH depletion by buthionine sulfoximine (BSO) treatment. The antioxidant trolox partially prevented the apoptosis and necrosis, while diallylsulfide, a CYP2E1 inhibitor, was fully protective. Damage to mitochondria appears to play a role in the CYP2E1- and BSO-dependent toxicity. CYP2E1-overexpressing cells showed increases in total GSH levels, GSH synthetic rate and in gamma-glutamylcysteine synthetase (GCS) mRNA. This GCS increase was due to transcriptional activation of the GCS gene and could be blocked by certain antioxidants. Activity, protein and mRNA levels for other antioxidants such as catalase, alpha- and microsomal glutathione transferases were also increased in the E47 cells. Up-regulation of these antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. These oxidants are diffusable and were able to elevate collagen type I protein in a co-culture system consisting of the E47 cells + rat hepatic stellate cells. Such interactions between CYP2E1, mitochondria and altered GSH homeostasis, and elevation of collagen levels, may play a role in alcohol-induced liver injury.
 ...
PMID:CYP2E1-dependent toxicity and up-regulation of antioxidant genes. 1117 76


1 2 3 4 Next >>