Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The constituent amino acids of reduced glutathione (GSH), GSH itself, and D-alpha-tocopherol inhibited 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activity in mouse epidermis in vivo and in vitro. The inhibitory effects of cysteine (Cys), GSH and D-alpha-tocopherol on ODC induction were proportional to their abilities to decrease the incidence of skin tumors in the initiation-promotion protocol. Moreover, the ability of the constituent amino acids of GSH and GSH to inhibit TPA-induced ODC activity correlated well with their ability to increase the ratio of GSH/oxidized glutathione (GSSG) in isolated epidermal cells. In vitro, various treatments with 1 mM GSH, 1 mM glutamic acid (Glu), 1 mM glycine (Gly), 0.4 mM Cys and/or 0.2 mM cystine (CysCys) inhibited dramatically the sharp decline in the intracellular ratio of GSH/GSSG caused by 0.1 microM TPA. Since the inhibitory effects of Cys on both the decrease in the ratio of GSH/GSSG and the induction of ODC activity by TPA were greatly reduced by the inhibitors of gamma-glutamyl transpeptidase and gamma-glutamylcysteine synthetase, it is suggested that some of the inhibitory effects of Glu, Cys and Gly on tumor promotion could result from their interference with the metabolism of the tripeptide GSH, a natural antioxidant which inhibits chemical carcinogenesis. The free radical scavenger D-alpha-tocopherol, which did not alter directly the intracellular ratio of GSH/GSSG, also prevented completely the decrease in the ratio of GSH/GSSG caused by TPA. These results, therefore, suggest that GSH level-raising agents and other antioxidants might inhibit by diverse means the effects of TPA on GSH metabolism and skin tumor promotion.
Carcinogenesis 1985 Apr
PMID:Inhibitory effects of glutathione level-raising agents and D-alpha-tocopherol on ornithine decarboxylase induction and mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. 285 27

The regulation of glutathione and various glutathione-dependent enzymes has been studied in two ovarian adenocarcinoma cell lines derived from a patient before (PE01) and after (PE04) the onset of drug resistance to cis-platinum, chlorambucil and 5-fluorouracil. Reduced glutathione levels were higher in the drug resistant cells (PE04). This could possibly be attributed to a much higher (6.5-fold) gamma-glutamyl-transpeptidase activity. In addition, glutathione-S-transferase (GST) and glutathione peroxidase were 2.9- and 2.3-fold higher in this cell line. Analysis of the GST subunit composition showed both cell lines contained high levels of the acidic GST and lower concentrations of a basic isozyme. The difference in GST activity between PE01 and PE04 did not appear to be related to the levels of these GST subunits. GSH, glutathione peroxidase and gamma-glutamylcysteinyl synthetase were all found to be regulated during the cell cycle, higher levels being detected in logarithmic versus confluent cultures of PE01 and PE04 and MCF7. This did affect some of the differences between PE01 and PE04 and therefore may be a contributing factor to the differential sensitivity of these cells to cytotoxic compounds. The above data provide the first evidence that tumour cells obtained from a patient before and after the onset of drug resistance have significant differences in glutathione-dependent enzyme content.
Carcinogenesis 1988 Jul
PMID:Glutathione and glutathione-dependent enzymes in ovarian adenocarcinoma cell lines derived from a patient before and after the onset of drug resistance: intrinsic differences and cell cycle effects. 289 6

The present studies determined the impact of dietary selenite on glutathione homeostasis in liver and mammary tissue and its relationship to biliary excretion of 7,12-dimethylbenz(a)anthracene (DMBA) conjugates. In Experiment 1, liver and mammary tissue concentration of reduced glutathione (GSH) and activities of gamma-glutamylcysteine synthetase (GCS), glutathione reductase (GR) and glutathione S-transferases (GST) were positively correlated with tissue selenium concentration in female rats fed semipurified diets supplemented with sodium selenite (0.05 to 4 mg Se/kg). The magnitude of the response was dependent upon total selenite intake and the tissue examined. Glutathione peroxidase activity did not correlate with tissue GSH concentration. Because both selenite and BHT have been reported to elevate liver GSH, Experiment 2 compared these agents (4 mg Se/kg and 6 g/kg BHT/kg, respectively) on the biliary excretion of DMBA metabolites. Five major biliary DMBA conjugates, three GSH and two beta-glucuronide, were identified. Dietary addition of selenite or BHT enhanced the excretion of these DMBA conjugates by over 100% during the 15-h collection period. These investigations suggest that dietary selenium can alter the concentration of GSH and the activities of three glutathione-dependent enzymes in mammary and liver, accounting for part of the expanded biliary excretion of DMBA conjugates. Enhanced biliary loss of DMBA conjugates likely relates to the reported depression in DMBA binding to mammary cell DNA and the inhibition of DMBA carcinogenesis caused by dietary selenite.
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PMID:Dietary selenite modifies glutathione metabolism and 7,12-dimethylbenz(a)anthracene conjugation in rats. 790 18

The concentration of glutathione (GSH) and the expressions of gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase (GGT) were assessed in rat embryo fibroblasts (REF) displaying various stages of X-ray-induced transformation. A secondary culture of REF cells was irradiated, and a normal-immortalized cell line (X-REF-23) was isolated. Chronic exposure of X-REF-23 cells to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) yielded cells (X-REF-23-TP) capable of benign tumor formation in nude mice. These cells exhibited GSH concentrations and gamma-glutamylcysteine synthetase heavy subunit mRNA levels that were approximately 50% less than those measured in X-REF-23 cells. Neither X-REF-23 nor X-REF-23-TP cells exhibited detectable GGT mRNA or activity. Administration of 3 Gy of X-rays followed by chronic TPA treatment yielded cells (X-REF-23-TPX) capable of malignant tumor formation in nude mice. These cells expressed GGT mRNA and Concanavalin-A minus GGT activity. One TPX clone (X-REF-23-TPX.1) was chosen for further characterization. Northern blotting of X-REF-23-TPX.1 cells indicated that gamma-glutamylcysteine synthetase heavy subunit mRNA levels were similar to those of X-REF-TP cells. X-REF-23-TPX.1 cells contained nearly the same amount of GSH as X-REF-23 cells. However, the ability of diethylmaleate (DEM) to deplete GSH was diminished in X-REF-23-TPX.1 cells compared with X-REF-23 cells. Furthermore, exposure of X-REF-23-TPX.1 cells to DEM stimulated GSH resynthesis such that the GSH concentration exceeded control values during exposure. The resynthesis of GSH during a DEM exposure was found to be dependent upon the expression of GGT, as demonstrated by inhibition with AT-125. These experiments indicate that ionizing radiation can lead to elevated constitutive expression of GGT in transformed REF cells and that expression of GGT activity was responsible for the increased rate of GSH repletion observed in X-REF-23-TPX.1 cells.
Carcinogenesis 1994 Jul
PMID:Genes regulating glutathione concentrations in X-ray-transformed rat embryo fibroblasts: changes in gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase expression. 791 22

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.
Carcinogenesis 1994 Oct
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 purpose of this investigation was to explore the reason why nickel chloride enhances the cytotoxicity and genotoxicity of ultraviolet (UV) light, but not that of methyl methanesulfonate (MMS) in Chinese hamster ovary cells. The cellular glutathione content was increased by treatment with MMS or nickel, but not with UV. Post-treatment with nickel synergistically raised the cellular glutathione content in MMS-treated cells; this phenomenon was not observed in UV-irradiated cells. Preventing cellular glutathione induction by buthionine sulfoximine increased the cytotoxicity, the frequency of sister chromatid exchange and prolonged the cell cycle in cells treated with nickel or MMS plus nickel. Pretreatment with N-acetylcysteine, a glutathione precursor, increased the clonogenic survival of cells treated with UV plus nickel. In vitro assays indicated that nickel could inhibit oligonucleotide ligation and the repair synthesis of UV- or MMS-treated plasmids and glutathione could relieve nickel inhibition. These results suggest that the enhancement by nickel of UV cytotoxicity and genotoxicity may be due to its inhibition of DNA repair, whereas treating cells with MMS plus nickel increased cellular glutathione levels, which may help in neutralizing the toxicity of nickel. The results also suggest that the activity of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione biosynthesis, may be increased by treatment with MMS, nickel and more so with MMS plus nickel.
Carcinogenesis 1994 Dec
PMID:Glutathione can rescue the inhibitory effects of nickel on DNA ligation and repair synthesis. 800 Dec 39

We have recently shown that multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCS) heavy subunit genes are coordinately overexpressed in cisplatin-resistant human leukemia cells (T. Ishikawa et al. J. Biol. Chem., 271: 14981-14988, 1996). Using the RNase protection assay, we examined expression levels of these genes in colon tumor and nontumorous biopsy specimens from 32 cancer patients who had not been treated with chemotherapy. Increased mRNA levels (P < 0.001) of MRP and gamma-GCS genes were observed in 16 (50%) and 20 (62%) tumor samples, respectively. More importantly, all of the 16 (100%) MRP-overexpressing tumor specimens also exhibited higher levels of gamma-GCS mRNA than those in the matched nontumorous specimens. The correlation coefficient between MRP and gamma-GCS mRNA levels was r = 0.78 for all of the tumor samples studied. These results strongly suggest that MRP and gamma-GCS genes are coordinately up-regulated during colorectal carcinogenesis.
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PMID:Frequent coordinated overexpression of the MRP/GS-X pump and gamma-glutamylcysteine synthetase genes in human colorectal cancers. 870 99

Glutathione metabolism was studied in rat liver during diethylnitrosamine (DEN) carcinogenesis. Some studies were also made in foetal rat liver. Endogenous GSH and non-protein thiols concentrations are increased in DEN-treated rats when compared to non-treated rats but no differences were found in cysteine, total thiols and protein thiols concentration. In foetal liver GSH concentration is only 35% of that in DEN-treated rat liver. The activities of several enzymes involved in glutathione metabolism are changed in DEN-treated rats. gamma-Glutamyl transferase activity and cysteine formation from GSH by liver homogenates is increased sevenfold. gamma-Glutamylcysteine synthetase activity, initial rate of [35S]cysteine incorporation in gamma-glutamylcysteine and initial rate of GSH formation from [35S]cysteine are increased two-fold. Cytosolic GSH S-transferase activity is increased twofold in DEN-treated rats and so GSH S-conjugates concentration is probably also increased. In foetal rat liver gamma-glutamyl transferase activity is about the same but gamma-glutamylcysteine synthetase activity is only 10% of that in DEN-treated rat liver. The increased GSH concentration in DEN-treated rat liver is probably due to the simultaneous increase in the activities of gamma-glutamyl transferase and gamma-glutamylcysteine synthetase. Blood plasma total glutathione is increased 1.4 times in DEN-treated rats, but no differences are found in GSH hepatic arteriovenous gradient. This associated with the increased gamma-glutamyl transferase activity suggests that sinusoidal GSH efflux is increased in DEN-treated rats.
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PMID:Glutathione metabolism in hepatomous liver of rats treated with diethylnitrosamine. 912 81

The antischistosomal agent oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] has been shown to inhibit chemically induced carcinogenesis in a variety of animal models. Of greatest interest is its unique ability to protect several target organs from structurally diverse carcinogens. Molecular and biochemical studies suggest that oltipraz affords cellular protection by inducing the expression of a battery of Phase II detoxification enzymes. Induction of glutathione S-transferase, gamma-glutamylcysteine synthetase and DT-diaphorase has been observed in human tissues following the administration of a single oral dosage of oltipraz. Preclinical and clinical data continue to support the development of oltipraz as a chemopreventive agent for clinical usage.
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PMID:Chemopreventive activity of oltipraz. 959 27

Pentachlorobenzene (PeCB) is an important environmental contaminant derived primarily from the by-product contamination of the popular fungicides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoting activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethylnitrosamine (200 mg/kg body weight) and 2 weeks later were administered 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 days/week. At the end of week 3, rats were subjected to a partial hepatectomy. Results showed that PeCB, at both doses, significantly increased both the number and area of glutathione S-transferase pi (GST-P) foci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In addition to increases in preneoplastic foci, liver glutathione concentrations and glutathione-associated enzymes showed significant changes in animals treated with PeCB. Glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentrations corresponded with the increase in GR activity with decreases of 40 and 30% in the low and high dose groups, respectively. No significant changes were detected in reduced glutathione concentrations. Together with changes in GR and gamma-GCS expression, a decrease in GST-P foci around the central veins was significant (P = 0.004) at the high dose. In these animals, 26% of the foci were classified as centrilobular whereas 37 and 39% of the foci were centrilobular in the low dose and control groups, respectively. Because of the co-localized nature of the changes in glutathione-associated enzymes and the decreased incidence of centrilobular foci, our results suggest that the reduced cellular environment may ultimately play a role in negatively selecting for foci growth.
Carcinogenesis 1998 Oct
PMID:Evidence for hepatocarcinogenic activity of pentachlorobenzene with intralobular variation in foci incidence. 980 69


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