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)

Karyotype, mitochondrial ultrastructure and several enzymatic activities were studied in two clones, D22 and D27, from SV40-transformed rabbit chondrocytes. Similar chromosome alterations, with recurrent losses and gains were observed at the various passages. Mitochondria were rare, with increase in size and crest alterations. By comparison to non-transformed rabbit chondrocytes, activities of superoxide dismutase 1 and 2 (SOD) and glutathione peroxidase were increased, those of glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase fluctuated according to passages, thymidylate synthase decreased, thymidine kinase and hypoxanthine-phosphoribosyl-transferase increased and the ratio lactate dehydrogenase B/A increased. In most cases, these variations were correlated with the number of chromosomes carrying the genes encoding for corresponding enzymes. These results, compared to those obtained in SV40-transformed human fibroblasts, demonstrate that the two cell types behave differently for detoxication systems against oxygen radicals, in particular for SOD2 activity, and have opposite imbalances of chromosomes carrying the corresponding genes.
Carcinogenesis 1992 May
PMID:Chromosomal, mitochondrial and metabolic alterations in SV40-transformed rabbit chondrocytes. 131 10

Treatment of rats with a single carcinogenic dose of CdCl2 (i.e., 30 mumol/kg) caused severe hemorrhagic damage in the testis within the first 12 h after the metal. Subsequently, atrophy with calcification developed in the next 2-3 mo. Atrophied tissues regenerated during the 1 yr after exposure. Twelve hours after exposure to the Cd treatment, lipid peroxidation levels, Fe content, and cellular production of H2O2 were remarkably elevated in testicular Leydig cells, the target cell population for Cd carcinogenesis. At the same time, glutathione peroxidase activity rose, glutathione reductase and catalase activities were reduced, and superoxide dismutase activity was unchanged. Xanthine oxidase activity in Leydig cells was also elevated at 6 and 9 h after the Cd treatment. Reduced glutathione in testes was decreased and oxidized glutathione was increased 12 h after exposure to the metal. These facts suggest that the carcinogenic doses of Cd induced oxidative stress while compromising cellular defense mechanisms against such stress. Therefore, active oxygen species such as H2O2 may have an important role in the initiation of carcinogenesis within the target cell population.
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PMID:Role of oxidative stress in single-dose, cadmium-induced testicular cancer. 152 11

A model of liver hyperplastic noduligenesis was induced in rats in vivo by long-term administration of thioacetamide (TAM; 100 mg/kg day i.p.). Three doses of 50 mg/kg of an antitumoral rhodium(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Blood and liver were obtained from either TAM, Rh(III) complex or TAM plus Rh(III) complex-treated rats in order to determine the interaction of both (tumoral and antitumoral) substances with the biochemical pathways related to glutathione redox cycle, enzyme activities involved in the oxidative stress coupled to the NADPH/NADP pair and enzymes related to the mono-oxygenase P450 system. The results showed that TAM induced an imbalance between the activities of glutathione-coupled enzymes. Glutathione reductase activity increased along with the intoxication, while glutathione peroxidase activity decreased. Alterations in the activity of soluble glutathione peroxidase were parallel to those of catalase. These results, together with decreased activities of enzymes related to cytochrome P450 mono-oxygenase system, NADPH cytochrome P450 reductase and NADH cytochrome b5 reductase, suggest that liver cells are not protected against the peroxidative stress produced by chronic administration of TAM. The Rh(III) complex did not produce significant changes in the parameters assayed when administered alone. When this complex was administered to TAM-treated rats, significant restoration of the following activities was observed: those of NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and malic enzyme), that of glutathione reductase (NADPH-consuming enzyme), NADPH-cytochrome P450 reductase and total catalase. These results, together with others in previous studies, suggest that the altered liver function induced by chronic administration of TAM can be partially restored by this rhodium complex. The mechanisms by which this complex counteracts the TAM-induced changes have not yet been established.
Carcinogenesis 1991 Feb
PMID:Alterations in hepatic peroxidation mechanisms in thioacetamide-induced tumors in rats. Effect of a rhodium(III) complex. 167 54

Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. These highly reactive compounds can act as initiators and/or promoters, cause DNA damage, activate procarcinogens, and alter the cellular antioxidant defense system. Antioxidants, the free radical scavengers, however, are shown to be anticarcinogens. They function as the inhibitors at both initiation and promotion/transformation stage of carcinogenesis and protect cells against oxidative damage. Altered antioxidant enzymes were observed during carcinogenesis or in tumors. When compared to their appropriate normal cell counterparts, tumor cells are always low in manganese superoxide dismutase activity, usually low in copper and zinc superoxide dismutase activity and almost always low in catalase activity. Glutathione peroxidase and glutathione reductase activities are highly variable. In contrast, glutathione S-transferase 7-7 is increased in many tumor cells and in chemically induced preneoplastic rat hepatocyte nodules. Increased glucose-6-phosphate dehydrogenase activity is also found in many tumors. Comprehensive data on free radicals, antioxidant enzymes, and carcinogenesis are reviewed. The role of antioxidant enzymes in carcinogenesis is discussed.
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PMID:Free radicals, antioxidant enzymes, and carcinogenesis. 219 55

A large number of human tumor cell lines of various origins have been investigated with respect to expression of glutathione-linked enzymes in the cytosol fraction. The amounts of the different enzymes were estimated by use of activity measurements and by silver staining or immunoblot analysis after electrophoresis of cytosol fractions purified by affinity chromatography on S-hexylglutathione Sepharose. Class Pi glutathione transferase was the most abundant enzyme in most tumor cells; the cell lines HepG2 and Raji were exceptions in not expressing significant amounts of this enzyme. HepG2 cells derive from hepatocytes, which normally do not express the class Pi enzyme, whereas Raji cells originate from B-lymphocytes, which normally do express a class Pi glutathione transferase. The highest level of the class Pi transferase, in terms of protein reacting with antibodies as well as enzyme activity, was noted in the colon carcinoma cell line LS174T. Hu549Pat cells, EBV-transformed B-lymphocytes, also expressed high levels of a protein reacting with antibodies specific for class Pi glutathione transferases, but did not display any significant activity with ethacrynic acid, a substrate characteristic for this class. Class Alpha and class Mu glutathione transferases, in cell lines expressing these isoenzymes, were present in significantly lower concentrations than the class Pi enzyme. Most of the tumor cells contained a class Alpha transferase composed of 27.5 kd subunits, which has the physicochemical and immunological properties of the most basic glutathione transferase found in human skin. In several cell lines, a protein was detected with an apparent subunit Mr value of 30 kd that was tentatively identified as an additional class Alpha glutathione transferase not previously described. In addition, other glutathione-linked enzyme activities, namely glutathione peroxidase, glutathione reductase and glyoxalase I, were assayed with specific substrates in the cytosolic fraction of the tumor cells; glyoxalase I could also be estimated semiquantitatively by silver staining of SDS-PAGE cells after affinity chromatography. Like the glutathione transferases, these enzymes displayed distinctly different levels of expression in the various cell lines. Thus, virtually every cell line was found to have a unique pattern of glutathione-linked enzymes, suggesting that the resistance phenotypes of the cells differ accordingly.
Carcinogenesis 1990 Sep
PMID:Differences among human tumor cell lines in the expression of glutathione transferases and other glutathione-linked enzymes. 240 Oct 46

At variance with Cr(III), Cr(VI) compounds easily cross cell membranes and exert genotoxic effects. No metabolic oxidation of Cr(III) could be detected, whereas Cr(VI) reduction was observed in the presence of body fluids and subcellular fractions of various tissues from several animal species. The differential efficiency of this process may account for the selection of target tissues in Cr(VI) carcinogenesis. For instance, reduction by saliva and gastric juice may explain a lack of carcinogenicity by the oral route; reduction inside erythrocytes may explain a lack of carcinogenicity at a distance from administration sites; reduction by the epithelial-lining fluid of terminal airways and by alveolar macrophages may be consistent with the occurrence of thresholds in lung carcinogenesis. Liver preparations displayed the top efficiency in reducing Cr(VI), whereas skeletal muscle, i.e., a typical target in experimental Cr(VI) carcinogenesis, had no detectable activity. Bronchial tree and peripheral lung parenchyma preparations from almost 100 individuals reduced Cr(VI) to a variable extent. The efficiency of lung parenchyma and of isolated alveolar macrophages was enhanced in cigarette smokers. In rats, Cr(VI) reduction by lung preparations was significantly stimulated by the repeated i.t. instillation of Cr(VI) itself. Among the electron donors (chiefly GSH) and enzymatic mechanisms responsible for the intracellular Cr(VI) reduction, such as cytochrome P-450 reductase, glutathione reductase, and aldehyde oxidase, an important role can be ascribed to cytosolic DT diaphorase activity, usually catalyzing a 2-electron reduction.
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PMID:Metabolic reduction of chromium, as related to its carcinogenic properties. 248 84

Dietary supplementation of vitamin C to diethylstilbestrol (DES)- or estradiol-treated male Syrian hamsters is known to inhibit renal carcinogenesis by approximately 50%. To elucidate the mechanism of inhibition, the influence of administration of vitamin C on a series of previously described biochemical markers of kidney carcinogenesis was investigated. Hamsters were stratified into four groups: (i) untreated controls; (ii) vitamin C-treated; (iii) estrogen-treated; and (iv) estrogen plus vitamin C-treated animals. Concomitant administration of vitamin C and diethylstilbestrol (DES) decreased concentrations of the major DES-DNA adduct by 70-90% in liver, kidney and testis than those receiving DES only. Diethylstilbestrol-4',4"-quinone has previously been shown to be the genotoxic metabolite of DES responsible for DNA adduct formation in vivo. In vitro, vitamin C reduced diethylstilbestrol-4',4"-quinone to cis- and trans-diethylstilbestrol in a dose-dependent fashion. Changes in activities of quinone reductase, catalase, superoxide dismutase and of glutathione metabolizing enzymes (glutathione peroxidase, glutathione reductase, gamma-glutamyl transpeptidase and glucose-6-phosphate dehydrogenase) in response to vitamin C were not observed or not sufficiently large to account for the 50% decrease in tumor incidence. No differences were detected in indirect estrogen-induced kidney DNA adducts in response to vitamin C treatment. It is concluded that vitamin C inhibits estrogen-induced carcinogenesis by reducing concentrations of estrogen quinone metabolites and their DNA adducts.
Carcinogenesis 1989 Nov
PMID:Mechanism of inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by vitamin C. 257 56

The effect of vitamin E on cytotoxicity induced by Na2CrO4 was evaluated by colony-forming assay using Chinese hamster V-79 cells. Pre-treatment with alpha-tocopherol succinate (vitamin E) for 24 h prior to exposure to Na2CrO4 resulted in a marked decrease in the cytotoxicity caused by this compound. The reduction of chromate-induced cytotoxicity was observed at all concentrations of Na2CrO4 (5-15 microM), and the protective effect increased with higher concentrations of vitamin E (5-25 microM). The level of glutathione reductase activity, which is capable of reducing chromate, was not affected by cellular pre-treatment with vitamin E. However, Na2CrO4 decreased glutathione reductase activity in a concentration-dependent fashion (5-15 microM) and pretreatment with vitamin E resulted in a significant recovery of enzyme activity suppressed by Na2CrO4, suggesting that this enzyme inhibition is linked to the cytotoxicity of this metal. Electron spin resonance studies showed that a paramagnetic chromium (V) complex was formed in cells treated with Na2CrO4, and that cellular pre-treatment with vitamin E reduced the formation of this chromium (V) intermediate. These results indicate that vitamin E protects cells from chromate-induced cytotoxicity as well as from enzyme inhibition, and also suggest that Na2CrO4-induced cytotoxicity is mediated by the generation of a reactive intermediate.
Carcinogenesis 1989 Apr
PMID:Effect of vitamin E on survival, glutathione reductase and formation of chromium (V) in Chinese hamster V-79 cells treated with sodium chromate (VI). 264 68

Target organ-specific estrogen-induced DNA adducts were previously shown to precede renal carcinogenesis in Syrian hamsters. Because estrogens induced these DNA modifications, but were not part of the adduct structure, free radical activation of endogenous electrophiles was postulated as a mechanism of tumor induction by estrogens. In the present study, the activities of enzymes which detoxify reactive intermediates were studied in liver and kidney of hamsters treated with estradiol for 1, 2, and 4 mo and in untreated controls. These studies were done to detect oxidative stress in the target organ of carcinogenesis. In the estrogen-exposed hamster kidney (1, 2, and 4 mo), activities of glutathione peroxidases I and II were significantly increased. The activity of catalase was decreased compared to those in untreated controls. In livers which are not the target organ of carcinogenesis, treatment of hamsters with estrogen for 1, 2, and 4 mo resulted in changes of activities of glutathione peroxidases I and II and catalase, which were opposite to the pattern found in the kidney. Activities of superoxide dismutase, glutathione reductase, glucose-6-phosphate dehydrogenase, gamma-glutamyl transpeptidase, and glutathione transferase in estradiol-treated hamster liver and kidney did not differ significantly from those in either liver or kidney of untreated age-matched controls. Fluorescent products of lipid peroxidation more than doubled in the kidney, but not in the liver of hamsters treated with estradiol for 1 mo. It is concluded that the increases in glutathione, in the activity of glutathione peroxidase, and in products of lipid peroxidation in the kidneys of hamsters treated chronically with estrogen all point towards elevated levels of oxidative stress.
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PMID:Changes in activities of free radical detoxifying enzymes in kidneys of male Syrian hamsters treated with estradiol. 292 1

Chemically induced rat liver nodules and cancers characteristically demonstrate a limited capacity to activate xenobiotics to reactive species mainly because of decreased amounts of cytochrome P-450. These lesions also show enhancement of xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and diethylnitrosamine-induced mouse liver tumors for nine enzyme activities commonly reported to be altered in chemically induced rat liver nodules and cancers. The activities of benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl transferase (EC 2.4.1.17) in microsomes from spontaneous tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced tumors. The activities of DT-diaphorase (EC 1.6.99.2), glutathione reductase (EC 1.6.4.2), glutathione S-transferase (EC 2.5.1.18), and glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.
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PMID:Xenobiotic metabolizing enzymes in genetically and chemically initiated mouse liver tumors. 308 73


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