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)

Methapyrilene ([14C]MPH) was found to bind to calf thymus DNA only after activation by both rat liver microsomes and NADPH. The cytochrome P-450 inhibitors 2,4-dichloro-6-phenylphenoxyethylamine, 2-diethylaminoethyl-2,2-diphenylvalerate and metyrapone inhibited binding, but methimazole, a flavin-dependent monooxygenase inhibitor, had no effect. However, 1,2-epoxy-3,3,3-trichloropropane, an epoxide hydrolase inhibitor, decreased binding by 30%. Pre-treatment of rats with isosafrole, pregnenolone-16 alpha-carbonitrile or phenobarbital had little or no effect on binding while 3-methylcholanthrene pretreatment decreased binding by 37%. Incubations in the presence of either N-acetylcysteine, glutathione, catalase or glutathione-peroxidase decreased binding to DNA while superoxide dismutase had no effect. These data suggest that MPH is metabolically activated to a species which binds to DNA and that this activation may be mediated by cytochrome P-450 isozymes.
Carcinogenesis 1987 Oct
PMID:Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro. 311 19

Inflammation has long been associated with carcinogenesis, especially in the promotion phase. The mechanism of action of the potent inflammatory agent and skin promoter 12-tetradecanoyl phorbol-13-acetate (TPA) is unknown. It is thought that TPA selectively enhances the growth of initiated cells, and during this process, initiated cells progress to the preneoplastic state and eventually to the malignant phenotype. Many studies support the multistep nature of carcinogenesis, and a significant amount of evidence indicates that more than one genetic event is necessary for neoplastic transformation. Selective growth stimulation of initiated cells by TPA does not explain how further genetic events may occur by chronic exposure to this nongenotoxic agent. We and others have proposed that TPA may work, in part, by inciting inflammation and stimulating inflammatory cells to release powerful oxidants which then induce DNA damage in epidermal cells. Macrophages cocultured with target cells and TPA induce oxidized thymine bases in the target cells. This process is inhibited by both catalase and inhibitors of lipoxygenases, suggesting the involvement of both H2O2 and oxidized lipid products. Furthermore, macrophage populations that release both H2O2 and metabolites of arachidonic acid (AA) are more efficient at inducing oxidative DNA damage in surrounding cells than populations which only release H2O2 or metabolites of AA. In vivo studies demonstrated that SENCAR mice, which are sensitive to promotion by TPA, have a more intense inflammatory reaction in skin than C57LB/6 mice, which are resistant to promotion by TPA. In addition, macrophages from SENCAR mice release more H2O2 and metabolites of AA, and induce more oxidative DNA damage in cocultured cells than macrophages from C57LB/6 mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inflammation, oxidative DNA damage, and carcinogenesis. 312 86

To better understand the role of free radicals in liver carcinogenesis, endogenous antioxidant defense systems and the susceptibility of membranes to lipid peroxidation were evaluated in early lesions and in malignant tumors induced by the Solt-Farber resistant hepatocyte protocol. These parameters were also measured in the liver surrounding these tumors. In comparison with the normal liver, both nodules and carcinomas show a different biochemical pattern consisting of decreased glutathione peroxidase (GSH peroxidase) and catalase activities plus increased glutathione reductase (GSSG reductase) activity. In contrast, 1 week after the application of the initiation-selection protocol, the liver displays a high level of glutathione (GSH), high GSSG reductase activity, a reduced production of malondialdehyde and no changes in superoxide dismutase and GSH peroxidase activities. These data suggest that the liver is well protected against reactive oxygen species. During the carcinogenic process, the liver parenchyma surrounding the altered foci recovers from most of the modifications induced by the initiation-selection treatment. These results add additional support for the hypothesis that the appearance of early alterations in the liver, after a carcinogenic treatment, might be an adaptive response to a hazardous environment in which selected cell populations are transformed into nodules and/or carcinomas.
Carcinogenesis 1988 Nov
PMID:Analysis of antioxidant defense systems during rat hepatocarcinogenesis. 318 Mar 39

Hydrazine is acutely neurotoxic, hepatotoxic and nephrotoxic; it is also carcinogenic to liver and lung in rodents. Administration of hydrazine results in formation of 7-methylguanine and O6-methylguanine in target organ DNA of rats, mice, hamsters and guinea-pigs. It has been suggested that hydrazine reacts with endogenous formaldehyde to form a condensation product which could be metabolized to a methylating agent. Solutions of 0.50 mM hydrazine and formaldehyde have, upon mixing, NMR spectra (300 MHz) consistent with the formation of formaldehyde hydrazone but not other possible condensation products such as tetraformyltriazine or formaldehyde azine. These same solutions evidencing hydrazone formation, when incubated in an in vitro system containing post-mitochondrial (S9), microsomal, cytosolic or mitochondrial cell fractions, resulted in the methylation of DNA guanine; S9 was the most active fraction. Neither the P-450 monooxygenase nor flavin monooxygenase systems appeared to be important in hydrazine/formaldehyde-induced methylation of DNA. However, sodium azide, cyanamide and carbon monoxide all inhibited S9-supported DNA methylation. Bovine liver catalase, a heme-containing cytochrome, readily transformed hydrazine/formaldehyde to a methylating agent. The data support formation of formaldehyde hydrazone as the condensation product of hydrazine and formaldehyde which is rapidly transformed in various liver cell fractions, perhaps by catalase and/or catalase-like enzymes, to a methylating agent.
Carcinogenesis 1988 Jan
PMID:Role of formaldehyde hydrazone and catalase in hydrazine-induced methylation of DNA guanine. 333 49

In light of recent studies implicating low catalase activities in the pathogenesis of the cancer-prone disease xeroderma pigmentosum (XP) we have measured catalase activity, protein levels, and mRNA concentrations in six XP fibroblast strains and three normal controls. Only one XP strain of complementation group A (XP1223) possessed significantly lower catalase by all three criteria. The other five XP strains (two XP variants, two strains of complementation group D, and one strain of complementation group C) possessed catalase levels which fell into the range of the interindividual variations of normal controls. We further assessed the total enzymatic antioxidant defense status by measuring the levels of copper, zinc, and manganese superoxide dismutase and glutathione peroxidase. None of these enzymes showed significant deviations from controls in XP cells. Our results do not support the notion that a deficient enzymatic antioxidant defense facilitates the establishment of a prooxidant state in XP upon exposure to near-UV. However, they do not argue against the participation of active oxygen in near-UV-induced carcinogenesis in XP.
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PMID:Antioxidant enzymes in xeroderma pigmentosum fibroblasts. 334 84

Topical treatment of female SENCAR mice with 12-O-tetradecanoylphorbol-13-acetate (TPA) reduced both dermal and epidermal catalase-specific activities 38% and 51% within 6 h and 18 h of promoter application, respectively. Dermal catalase activity recovered to control levels within 72 h of treatment whereas epidermal catalase activity remained suppressed. Activity measurements were also made in four subpopulations of keratinocytes prepared by Percoll gradient centrifugation that differed in their stages of differentiation. Catalase-specific activity increased with keratinocyte maturity and ranged from 45-54 U/mg protein for basal cell preparations to 252 U/mg protein for granular-squamous cell preparations. Pretreatment of the epidermis for 16-18 h with TPA (2 micrograms) uniformly reduced catalase-specific activity 46-52% in all keratinocyte subpopulations prepared by Percoll gradient centrifugation. Similarly, plots of catalase units per cell versus extracted protein per cell suggested 55-60% decreases in catalase activity in basal and spinous cell keratinocytes of TPA treated epidermis. Furthermore, catalase-specific activity in homogenates of whole epidermis (144-182 units/mg protein) was most similar to the activity of the granular/squamous keratinocyte subpopulation. Collectively, these studies suggest that: (i) TPA reduces the capacity for H2O2 detoxification by catalase throughout the epidermis; and (ii) activity measurements on unfractionated epidermal preparations may not be representative of the basal cell keratinocyte population.
Carcinogenesis 1988 Jul
PMID:Distribution of catalase and its modulation by 12-O-tetradecanoylphorbol-13-acetate in murine dermis and subpopulations of keratinocytes differing in their stages of differentiation. 338 43

Enzyme activities relating to H2O2 production (peroxisomal acyl-CoA oxidase) and degradation (catalase and glutathione peroxidase) were measured in the livers of male mice of the inbred strains C57BL/6J (C57) and C3H/HeJ (C3H) and their F1 hybrid, B6C3F1. Groups of the three genotypes were maintained on either a basal diet or one containing 0.1% of the peroxisome-proliferating agent, nafenopin, for six weeks. In both control and nafenopin-exposed groups, the C57 strain displayed higher acyl-CoA oxidase activity levels than the C3H mice, whereas the activity levels of catalase and glutathione peroxidase were not different for the two inbred strains. The groups of similarly fed B6C3F1 hybrids had intermediate values for acyl-CoA oxidase. Several other parameters relating to peroxisome proliferation did not differ among the three genotypes. Acyl-CoA oxidase levels in cultured hepatocytes from C57 mice were greater than those in hepatocytes obtained from the C3H strain during two days in culture and this difference was maintained for 4 days by nafenopin exposure. Acyl-CoA oxidase is central to the hypothetical H2O2 mechanism of peroxisome proliferator-induced hepatocarcinogenesis and, therefore, the genetic difference documented here may lead to a useful approach in testing this hypothesis.
Carcinogenesis 1988 Aug
PMID:Genetic differences in enzymes associated with peroxisome proliferation and hydrogen peroxide metabolism in inbred mouse strains. 340 42

Results from in vivo and in vitro studies showing that antioxidants may act as anticarcinogens support the role of active oxygen in carcinogenesis and provide impetus for exploring the functions of dietary antioxidants in cancer prevention by using in vitro models. We examined the single and combined effects of selenium, a component of glutathione peroxidase, and vitamin E, a known antioxidant, on cell transformation induced in C3H/10T-1/2 cells by x-rays, benzo[a]pyrene, or tryptophan pyrolysate and on the levels of cellular scavenging systems and peroxide destruction. Incubation of C3H/10T-1/2 cells with 2.5 microM Na2SeO3 (selenium) or with 7 microM alpha-tocopherol succinate (vitamin E) 24 hr prior to exposure to x-rays or the chemical carcinogens resulted in an inhibition of transformation by each of the antioxidants with an additive-inhibitory action when the two nutrients were combined. Cellular pretreatment with selenium resulted in increased levels of cellular glutathione peroxidase, catalase, and nonprotein thiols (glutathione) and in an enhanced destruction of peroxide. Cells pretreated with vitamin E did not show these biochemical effects, and the combined pretreatment with vitamin E and selenium did not augment the effect of selenium on these parameters. The results support our earlier studies showing that free radical-mediated events play a role in radiation and chemically induced transformation. They indicate that selenium and vitamin E act alone and in additive fashion as radioprotecting and chemopreventing agents. The results further suggest that selenium confers protection in part by inducing or activating cellular free-radical scavenging systems and by enhancing peroxide breakdown while vitamin E appears to confer its protection by an alternate complementary mechanism.
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PMID:Selenium and vitamin E inhibit radiogenic and chemically induced transformation in vitro via different mechanisms. 345 98

In order to understand the role in carcinogenesis of damage indirectly induced by chemical carcinogens, it is important to identify the primary DNA lesions. We have measured the formation and repair of one type of DNA modification, 5,6-dihydroxydihydrothymine (thymine glycol), following exposure of cultured human cells to the carcinogens N-hydroxy-2-naphthylamine or benzo(a)pyrene. The efficiency of production of thymine glycols in DNA by these carcinogens was compared to that by ionizing radiation and ultraviolet light. Thymine glycols were detected using a monoclonal antibody against this product in a sensitive immunoassay. We found that thymine glycols were produced in DNA in a dose dependent manner after exposure to the carcinogens and that their production was reduced if either catalase or superoxide dismutase or both were present at the time of treatment. The efficiency of thymine glycol production following exposure to the chemical carcinogens was greater than that following equi-toxic doses of radiation. Thymine glycols were efficiently removed from the DNA of human cells following treatment with either the chemical carcinogens, ionizing radiation or ultraviolet light.
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PMID:Production of thymine glycols in DNA by radiation and chemical carcinogens as detected by a monoclonal antibody. 347 81

This study was undertaken to investigate the hypothesis linking peroxisome proliferation with the production of reactive oxygen species and subsequent DNA damage. Hepatic peroxisomal proliferation was induced in male Wistar-derived rats by the administration of clofibrate, methyl clofenapate, di(2-ethylhexyl)phthalate, or its metabolite mono (2-ethylhexyl)phthalate (MEHP) for periods of up to 28 days. Genotoxicity was monitored using an alkaline elution technique to assay for DNA strandbreaks and cytotoxicity was monitored by measuring lipid peroxidation. Both parameters might be expected to be elevated if peroxisome proliferation is accompanied by an elevated level of oxygen free radicals within the cell. Enzyme measurements made on the livers of the treated rats showed that peroxisomal palmitoyl CoA oxidase activity was markedly increased over control whereas peroxisomal catalase activity was not. In addition, both the cytosolic glutathione peroxidase and superoxide dismutase activities were found to be lowered in the treated animals by up to 50 and 20% respectively. Despite such changes in enzyme activity, no evidence for increases in DNA strandbreaks or lipid peroxidation was obtained with any of the chemicals at any of the time points examined. DNA strandbreaks were also assayed on hepatocytes treated in culture with MEHP (0.5 mM) for 3 days and then exposed to inhibitors of DNA repair for 2 h immediately before assay. Again, no significant increase over controls was observed. Our data suggest that any increase in radical production in the livers of rats exposed to peroxisome proliferators is not large enough to give rise to a biologically significant degree of DNA damage and that the mechanism whereby such chemicals produce liver tumours in certain rodent species may be one other than simply DNA damage due to increased production of radical species.
Carcinogenesis 1987 Sep
PMID:Lack of DNA damage or lipid peroxidation measured in vivo in the rat liver following treatment with peroxisomal proliferators. 362 60


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