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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The disposition of the carcinogenic (+)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE] has been studied in isolated hepatocytes obtained from 3-methylcholanthrene-pretreated rats. In these cells different routes are acting in concert and contribute to diol-epoxide elimination. Conjugation of (+)-anti-BPDE with glutathione (GSH) and cytochrome P-450c-mediated metabolism of the diol-epoxide to 1- and 3-hydroxy-anti-BPDE (triol-epoxides) appears to be equally important. The reactive triol-epoxides undergo a number of secondary reactions, including covalent binding to cellular constituents, e.g. protein and GSH, and hydrolysis to pentahydroxyderivatives. The effective intracellular lifetime of (+)-anti-BPDE is approximately 1 min and comparable to that previously observed in hepatocytes obtained from uninduced animals.
Carcinogenesis 1989 Feb
PMID:The influence of cytochrome P-450 induction on the disposition of carcinogenic benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide in isolated cells. 249 11

Administration of ethionine resulted in a dose- and time-dependent enhancement of the activities of peroxisomal beta-oxidation, carnitine palmitoyltransferase and omega-oxidation, especially the 12-hydroxylation of lauric acid. The mitochondrial and, especially, the microsomal palmitoyl-CoA hydrolase activities were increased, whereas the peroxisomal and cytosolic activities were decreased. Ethionine administration decreased the catalase and urate oxidase activities in both a dose- and time-related manner. The liver cells and the volume fraction of cytoplasma decreased 40% in ethionine-exposed animals, whereas the average nuclei volume fraction increased approximately 50%. The volume fraction and the total number of mitochondria increased 1.5-fold after ethionine exposure and an accumulation of lipid in large droplets of the hepatocytes was observed. No proliferation of peroxisomes was observed after treatment; the volume fraction and the number of peroxisomes decreased. However, the size of peroxisomes in livers of ethionine-exposed rats tended to be greater than controls; a 1.5-fold increase in average size was observed. As there was no induction of the protein content of the bifunctional enoyl-CoA hydratase, an enzyme involved in peroxisomal beta-oxidation, it is considered that ethionine selectively stimulates the peroxisomal beta-oxidation due to increased peroxisome surface area rather than evoked a peroxisome proliferation capacity. Increased peroxisomal beta-oxidation was also observed in the kidney of ethionine-exposed rats at a dose of 750 mg/day/kg body weight. At that dose the amount of reduced glutathione (GSH) was significantly increased in kidney. The amount of GSH and the level of peroxisomal beta-oxidation were significantly increased in liver at an ethionine dose of 100 mg/day/kg body weight. These responses in liver were evident within 2 days of ethionine exposure and then leveled off whereas a significant increase in GSH and peroxisomal beta-oxidation in kidney was observed within 12 days. Whether the acute H2O2-generating peroxisomal oxidation of long-chain fatty acids in the liver may also make this organ susceptible to the long-term effects of low-dose ethionine and be an important step in the chain of events which eventually results in tumour development should be considered.
Carcinogenesis 1989 Jun
PMID:Changes in peroxisomes and mitochondria in liver of ethionine exposed rats: a biochemical and morphological investigation. 249 2

A single dose of 2 microCi [3H] aflatoxin B1 (AFB1) containing 20 micrograms AFB1 was administered to the lactating rat. This resulted in the excretion of AFB1-metabolites in the milk, which were transferred and distributed in many tissues of the offspring consuming milk for 48 h. An equal distribution of radioactivity in liver and lung of suckling rats as well as in their sub-cellular fractions was observed. No AFB1 metabolite binding was apparent with tissue DNA. However, considerable binding of aflatoxin residues was observed with protein followed by RNA. Three metabolites have been detected in the milk sample derived from the stomach of the suckling rats on thin layer chromatogram with Rf values of 0.2, 0.4 and 0.8. Pretreatment of lactating rats with phenobarbitone (PB: 80 mg/kg/3 days) prior to the administration of [3H]AFB1 caused an overall decrease in the radioactivity in the neonatal tissues, particularly lung and intestine (P less than 0.05). The fluorescent bands with Rf values of 0.2 and 0.4 were not visualized in the milk sample from the PB group. Subsequently, the binding of AFB1 residues to cellular macromolecules of neonatal tissues was decreased. PB treatment further resulted in lowering the glucuronide/sulphate conjugates of AFB1 in the milk consumed by suckling rats; AFB1-glutathione (GSH) conjugates were slightly increased. These results point out the possibility that aflatoxin metabolites bind to the tissues of offspring fed by mothers consuming aflatoxin contaminated diets thus leading to chronic effects.
Carcinogenesis 1989 Nov
PMID:Interaction of aflatoxin B1 metabolites with cellular macromolecules in neonatal rats receiving carcinogen through mother's milk. 250 93

Hydroquinone (HQ) may activate oxygen via redox cycles in biological systems and may also deplete glutathione (GSH). Both these reactions are potentially harmful, and we have studied their possible involvement in hydroquinone-induced development of gamma-glutamyltranspeptidase (GGT)-positive enzyme-altered foci in rat liver. The effect of HQ was compared to the effect of duroquinone, catechol, resorcinol and phenol. The dose was 100 mg/kg per day and the test substances were administered for 7-12 weeks in these foci experiments. HQ gave an increased number of foci and increased the foci volume, while none of the other compounds had any significant effect on these parameters. HQ, duroquinone and resorcinol were also tested at a higher dose level (200 mg/kg per day), but this dose gave a lower number of foci than the 100-mg dose. HQ, duroquinone and catechol induced single-strand breaks in hepatic DNA. Single doses of HQ (200 mg/kg) increased malondialdehyde excretion in urine, indicating in vivo lipid peroxidation. Duroquinone, phenol and resorcinol were negative with respect to malondialdehyde excretion. Catechol could not be properly tested as the 200-mg dose killed several animals. HQ and catechol induced hepatic ornithine decarboxylase activity. This effect was correlated to GSH depletion. An in vitro model for toxicity studies with hepatocytes from carcinogen-treated rats was also used. In this model HQ could be shown to be selectively toxic to GGT-negative cells in the presence of extracellular GSH. The toxicity was preceded by a rapid depletion of GSH. Catechol also depleted GSH and could be shown to be selectively toxic, but higher concentrations than those used for HQ had to be used. Duroquinone, phenol and resorcinol were not selectively toxic to GGT-negative cells. As duroquinone can be regarded as a more potent inducer of redox cycles than HQ, it can be concluded that the foci data provide no evidence for an involvement of redox cycles in HQ induced development of enzyme-altered foci. They suggest that GSH depletion may act to develop enzyme-altered foci, and the in vitro data indicate a mechanism by which GSH depletion and toxicity may induce this effect.
Carcinogenesis 1989 Mar
PMID:The role of GSH depletion and toxicity in hydroquinone-induced development of enzyme-altered foci. 256 22

The interaction of chromium(III) and chromium(VI) with the phosphate groups of di- and triphosphate nucleotides were examined by 31P-NMR spectroscopy. Chemical shifts of the phosphate groups, indicating the formation of Cr-nucleotide complexes, could only be detected with Cr(III). When Cr(III) was generated from Cr(VI) by reduction with an excess of glutathione, nearly the same chemical shifts could be observed. This indicates that glutathione is not capable of trapping Cr(VI) by reduction with subsequent formation of stable Cr-GSH complexes, thus preventing the binding of chromium to important target molecules as DNA or nucleotides. Using radioactively-labelled chromium no 51Cr(VI) bound to any nucleic acid, whereas 51Cr(III) bound in increasing order to poly(A).poly(U), calf thymus DNA and poly(G).poly(C). Furthermore, the melting temperature of nucleic acids increased in the same order only in the presence of Cr(III). Possible genotoxic consequences in vivo of the presented data in vitro concerning the binding of Cr(III) to sensitive molecular targets are discussed in detail.
Carcinogenesis 1989 Apr
PMID:Molecular interaction of different chromium species with nucleotides and nucleic acids. 270 14

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
Carcinogenesis 1989 Jun
PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Over the last few decades, free radicals have been increasingly implicated in biological processes including radiation effects, ageing, carcinogenesis, initiation and progression of various diseases, toxicity of chemicals and drugs. In this field Radiation Biology has played an important role in the development of both technical and cultural background, because it was very soon recognized the radical nature of processes following exposure to ionizing radiation. Several studies have pointed out the importance of both radicals, reacting with cellular targets, and endogenous thiols, mainly represented by glutathione, in controlling radiation responses of living cells. Experimental supports for such a role mainly rest on observations made on cell lines depleted of glutathione content because of a genetic defect or as result of a pharmacological manipulation. We present a study on the influence of endogenous and exogenous thiols on the correlation between lethal and mutational damage in mammalian cells. Survival (S) and induction of HPRT- mutation (M) were measured in cells irradiated with X-rays either after treatment with BSO or in the presence of MEA or GSH. In control experiments log of S is linearly correlated to M. Incubation with 1 mM BSO reduces cellular GSH content and produces an increase in radiosensitivity with regard to both lethal and mutagenic effects. In the presence of MEA a concentration dependent radioprotective effect can be observed on both end-points. GSH added to cells immediately or 90 min before irradiation only displays a slight protective effect on lethality. The yield of mutant cells is not significantly affected when GSH is added immediately before irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of thiols in lethal and mutational radiation damage. 275 Nov 90

This study deals with the role of glutathione transferase (GST)-mediated conjugation of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE) in two mammalian cell lines, human mammary carcinoma cells (MCF-7) and rat hepatoma cells (H4IIE), in relation to their capacity to metabolize (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)-BP-7,8-diol] to products that induce mutations in co-cultivated V79 cells. Both MCF-7 and H4IIE cells metabolized (-)-BP-7,8-diol to BPDE, but mutations in co-cultivated V79 cells were only detected with MCF-7 cells. However, depletion of glutathione (GSH) in H4IIE cells increased the mutagenicity of (-)-BP-7,8-diol to a similar level to that found with MCF-7 cells. Measurements of GST activity using GSH and post-microsomal supernatants from H4IIE, V79 and MCF-7 cells indicated a substantial difference in conjugation capacity. Although preparations from all three cell-lines showed GST activity with 1-chloro-2,4-dinitrobenzene as the substrate, GST activity towards BPDE could only be detected in supernatants from H4IIE cells. This is consistent with the presence of GST 7-7 an isoenzyme highly efficient in catalysing BPDE-GSH conjugation. The difference in GSH-conjugation activity towards BPDE was confirmed using intact H4IIE and MCF-7 cells in culture. These results indicate that GSH-conjugation plays a pivotal role in mutagenesis induced by polycyclic aromatic hydrocarbons (PAH). Accordingly, a deficiency in GSH-conjugation capacity may be regarded as one important factor in defining a target cell population with an increased risk for tumour initiation following exposure to PAH.
Carcinogenesis 1989 Sep
PMID:Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay. 276 61

An important biological function of glutathione (GSH) resides in the detoxication reactions mediated by enzymes such as glutathione-S-transferase (GSTs) and glutathione peroxidase (GPX). An increasing body of evidence implies that GSH and these enzymes play important roles in determining the sensitivity of tumours against cytotoxic drugs like quinone antibiotics, in particular adriamycin (Adr). In the present study, we have analysed the effects of cell-cycle on GSH and GSH-dependent enzymes in an attempt to explain cell-cycle specificity of these antileukaemic drugs which were shown to be involved in free-radical-type reactions. Determination of GSH, GST, GPX and superoxide dismutase in cell-cycle-enriched fractions of five different human myeloid leukaemia cell lines (KG1, K562, U937, ML-1 and ML-2) yielded results identical to those obtained in random cultures, which implies that neither GSH nor GSH-related enzymes are cell-cycle regulated. These findings argue against the presumption that cell-cycle specificity of cytotoxic drugs like Adr could be due to the glutathione-dependent metabolism in myeloid leukaemia cell lines.
Carcinogenesis 1989 Sep
PMID:Influence of cell cycle on glutathione-S-transferase, selenium-dependent glutathione peroxidase, superoxide dismutase and glutathione levels in human myeloid leukaemia cell lines. 276 62


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