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)

Diethyldithiocarbamate (DDTC) injected i.p. inhibits remarkably and in a dose-dependent manner 12-O-tetradecanoylphorbol-13-acetate (TPA)-decreased glutathione (GSH) peroxidase and TPA-induced ornithine decarboxylase (ODC) activities in mouse epidermis in vivo. DDTC is more potent in inhibiting these effects of TPA than 16 other antioxidants, free radical scavengers, thiol-containing compounds, and reduced glutathione (GSH) level-raising agents, even though some of these treatments are applied directly to the TPA-treated skin. DDTC also inhibits the effects of several structurally different tumor promoters and the greater GSH peroxidase and ODC responses produced by repeated TPA treatments. The inhibitory effects of DDTC on TPA-decreased GSH peroxidase and TPA-induced ODC activities are additive with those of Na2SeO3 and D-alpha-tocopherol (vitamin E). Interestingly, DDTC is a more effective inhibitor when it is administered after TPA, suggesting that DDTC may supplement, facilitate, and/or enhance the activity of the natural GSH-dependent detoxifying system protecting the epidermis against the oxidative challenge presumably linked to the tumor-promoting activity of TPA. When tested in the initiation-promotion protocols, DDTC inhibits to the same degree complete tumor promotion by TPA and stage 2 tumor promotion by mezerein, in relation with its identical inhibition of the GSH peroxidase and ODC responses to both TPA and mezerein. Moreover, the inhibition of the first stage tumor-promoting activity of TPA by DDTC may be attributed to its ability to inhibit TPA-induced DNA synthesis, a postulated component of the conversion phase of skin carcinogenesis when TPA is used as a stage 1 tumor promoter.
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PMID:Inhibition of multistage tumor promotion in mouse skin by diethyldithiocarbamate. 282 29

Evidence has been obtained that implicates the generation of reactive oxygen species as an early and critical event in the promotion of neoplastic transformation in mouse JB6 cells. The time courses for specific inhibition by CuZn-superoxide dismutase (CuZn-SOD) of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of neoplastic transformation in JB6 cells and for changes in antioxidant enzyme activities associated with TPA-exposure were examined. The antipromoting effect of CuZn-SOD was found to be critically dependent on the time of addition of CuZn-SOD relative to the start of a 14-day exposure of cells to TPA. Treatment of JB6 P+ Clone 22 and Clone 41 cells with CuZn-SOD for 18 h before, simultaneously with or up to 1 h after exposure to TPA, all inhibited promotion of transformation maximally. Delay of addition of CuZn-SOD by 2 h or more after the start of TPA treatment resulted in a marked decrease in the promotion inhibitory effect. CuZn-SOD added 24 or 48 h after TPA had no effect on promotion of transformation. Exposure of JB6 cells to 0.2- (superoxide anion radical) generated exogenously by the aerobic xanthine oxidase reaction resulted in promotion of neoplastic transformation that was prevented by concurrent addition of CuZn-SOD. Taken together these studies provide evidence that increased superoxide anion generation within the first 2 h following TPA exposure is an essential event in promotion of transformation in JB6 cells. Upon TPA exposure, JB6 Clone 41 cells exhibited time-specific activity changes in the cellular SOD, glutathione peroxidase (GSH-Px), and catalase. SOD and GSH-Px activities were reduced to 54% and 26% respectively of basal levels within 2 h of TPA treatment. GSH-Px activity recovered to basal levels within 4 h and CuZn-SOD within 48 h. Catalase activity was maximally reduced to 50% of basal within 1 h after TPA treatment and rebounded to greater than basal levels within 4 h. It is postulated that a c-kinase-dependent event induces rapid elevation of superoxide anion following TPA exposure and that this leads to reduced activity of antioxidant enzymes. Since antipromotion by exogenous CuZn-SOD is effective only during the first 2 h following TPA exposure, this suggests that the promotion-relevant 0.2- elevation is transient.
Carcinogenesis 1988 Feb
PMID:Early superoxide dismutase-sensitive event promotes neoplastic transformation in mouse epidermal JB6 cells. 282 3

With a view of elucidating the role of glutathione (GSH) in the biochemical pathways of the chromate-exposure related carcinogenesis, we carried out electron spin resonance (ESR) spectroscopic investigations of the chromate-GSH redox reactions. The ESR measurements, employing spin-traps, provide evidence for the involvement of the glutathione (GS) radical, as well as an isolable Cr(V)-glutathione intermediate. These results indicate a new mechanism for the reduction of chromate by GSH in in vitro cellular environment and help understand the (unexpected) increase in Cr(VI)-induced DNA strand breaks at elevated GSH levels.
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PMID:On the mechanism of the chromate reduction by glutathione: ESR evidence for the glutathionyl radical and an isolable Cr(V) intermediate. 284 69

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 effect of carcinogen treatment on gamma-glutamyl transpeptidase (GGT)-mediated hydrolysis of GSH to glutamate and cysteinylglycine in the blood and bile compartments was investigated in livers perfused in situ. Treatment of rats with 40 p.p.m. diethylnitrosamine (DEN) in the drinking water or 0.02% 2-acetylaminofluorene (AAF) in the diet for 50-60 days increased GGT activity in liver homogenates by 100 and 800% respectively. Bile flow and the sum of glutamate and glutathione (GSH) efflux into the bile of perfused livers was not affected by carcinogen treatment. However, the ratio of GSH to glutamate in bile was 2.1, 1.1 and 0.2 in livers from control, DEN- and AAF-treated rats respectively. Pretreatment with L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT125) decreased GGT activity in liver homogenates by about 85% and elevated the ratio of GSH to glutamate in the bile to 3.2 in all groups. Thus, the hydrolysis of GSH to glutamate in the bile of perfused livers correlated with the degree of induction of GGT by DEN and AAF treatments. Exogenous GSH (10 microM) infused into the portal vein of perfused livers from control, DEN- and AAF-treated rats was recovered completely in the effluent perfusate. Pretreatment with AT125 had no effect on the recovery of exogenous GSH in the effluent perfusate. Thus, metabolism of GSH in the blood space was not detected after short-term carcinogen treatment. To increase the possible hydrolysis of GSH in the perfusate, rats were treated for 130-180 days with DEN and GSH (60 microM) was infused into the hepatic artery of livers perfused simultaneously via the hepatic artery and portal vein. Only 50% of the infused GSH was recovered in the effluent perfusate of perfused livers from DEN-treated rats. In contrast, significantly more GSH (80-90%) was recovered from livers from control rats or DEN-treated rats that had received AT125 pretreatment. In addition AT125 pretreatment increased the basal rates of GSH efflux in livers from DEN-treated rats. Thus, DEN-induced GGT metabolizes GSH entering the liver via the hepatic artery. Furthermore, GGT may act to decrease the net efflux of GSH from perfused livers by causing the intraorgan recycling of GSH and its constituent amino acids.
Carcinogenesis 1987 Jul
PMID:Carcinogen treatment increases glutathione hydrolysis by gamma-glutamyl transpeptidase. 288 2

Reduced glutathione (GSH) is mutagenic in Salmonella in the presence of gamma-glutamyltranspeptidase (GGT), with the highest response obtained in strain TA102. Reduced cysteinylglycine, one of the products of GGT metabolism of GSH, is mutagenic in the absence of GGT. In strain TA102, GSH mutagenesis was dependent on molecular oxygen, enhanced by iron, inhibited by EDTA, desferrioxamine mesylate, mannitol, butylated hydroxyanisole, peroxidase and catalase, but not by superoxide dismutase. Binding of GSH or its GGT-dependent metabolites to DNA in vitro was not detected. This is consistent with a model of an indirect mechanism of mutagenesis, i.e. cleavage of GSH by GGT, followed by facile auto-oxidation of the resulting cysteinylglycine, with the production of free radicals which lead to the (pen)ultimate mutagen, H2O2.
Carcinogenesis 1988 May
PMID:Glutathione mutagenesis in Salmonella typhimurium is a gamma-glutamyltranspeptidase-enhanced process involving active oxygen species. 289 53

Hepatocyte resistance against glutathione (GSH) depleting xenobiotics was studied in an in vitro model. Hepatocytes were isolated from carcinogen treated rats that had received phenobarbital for three weeks. Isolated cells were incubated in GSH containing buffer with hydroquinone, which depleted GSH. Cells were then seeded on collagen coated plates and cultured overnight in complete medium. Attached cells were stained and the proportion of gamma-glutamyltranspeptidase (GGT)-positive cells was counted. It was found that toxicity related to GSH depletion increased the proportion of GGT-positive cells from 10-15% up to 40-60%, indicating that the toxicity mainly affected GGT-negative cells. GSH added to the buffer was essential for this effect. It is concluded that GGT may protect GGT-positive hepatocytes from GSH depletion and toxicity early during liver carcinogenesis.
Carcinogenesis 1988 Jul
PMID:gamma-Glutamyltranspeptidase-conferred resistance to hydroquinone induced GSH depletion and toxicity in isolated hepatocytes. 289 4

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 biochemical responses to 8-week supplementary treatment with selenium and/or vitamin E were evaluated in 41 patients with gynaecological cancer during cytotoxic chemotherapy, in Finland, a selenium-deficient country. After the control course of 1-day treatment with cytostat agents, 11 patients received a combination of selenium and vitamin E (sodium selenate, 200 micrograms/day + vitamin E, 300 mg/day), 11 received selenium (sodium selenate, 200 micrograms/day) and seven received vitamin E (300 mg/day) as supplementary therapy, while 12 patients had no supplementary drugs. Sodium selenate alone and combined with vitamin E significantly increased the serum selenium levels, but the activity of serum glutathione peroxidase (GSH-Px) increased significantly only in the selenium- and vitamin E-treated patients with low initial GSH-Px activity. The cytotoxic chemotherapy did not change the activity of GSH-Px, while the concentrations of lipid peroxides decreased. Sodium selenate alone or with vitamin E did not modify this decrease. Sodium selenate alone significantly decreased the capacity of the platelets to produce thromboxane A2; it increased high-density lipoprotein cholesterol levels and prevented the cytotoxic-chemotherapy-associated increase of creatine kinase. Selenium supplementation might thus be beneficial during cytotoxic chemotherapy in ovarian cancer patients with low selenium levels.
Carcinogenesis 1989 Feb
PMID:Supplementation with selenium, vitamin E and their combination in gynaecological cancer during cytotoxic chemotherapy. 291 78

Labeling studies with 75selenium (75Se) have suggested the existence of selenium-binding proteins in addition to glutathione peroxidase (GSH-Px) in rodent tissues. Three selenium-binding proteins of apparent mol. wt 56, 14 and 12K on SDS-PAGE were isolated from mouse liver using Sephadex G-150 and DEAE-Sephadex chromatography. The proteins were electroeluted from SDS-PAGE gels and injected into rabbits to elicit antibodies. Western immunoblot experiments indicated that the 56K protein was distinct from the 14 and 12K proteins. The latter two proteins appeared to be immunologically related, perhaps as differentially processed variants. The 56 and 14/12K proteins appeared to be distinct from GSH-Px and the 57K plasma selenium-binding proteins. These results indicate that the mouse liver contains at least two selenium-binding proteins distinct from GSH-Px. The existence of the antibodies should permit experiments which help to examine the role of these proteins in the biological function of selenium in mammals.
Carcinogenesis 1989 Mar
PMID:Evidence for two selenium-binding proteins distinct from glutathione peroxidase in mouse liver. 292 98


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