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)

There is a considerable interest in developing potent and safe hypolipidemic drugs for the prevention and management of coronary heart disease in man. In rodents, many of these hypolipidemic compounds induce hepatomegaly, proliferation of peroxisomes and a polypeptide with an approximate mol. wt. of 80000 in liver cells. In the present study, we have examined 10 hypolipidemic compounds for the induction of peroxisome proliferation associated 80000 mol. wt. polypeptide (polypeptide PPA-80), peroxisomal enzymes and peroxisome proliferation in rat liver, in view of the emerging evidence that hepatic peroxisome proliferators as a class are carcinogenic in rats and mice. All ten compounds, fenofibrate (isopropyl-[4-(p-chlorobenzoyl)2-phenoxy-2-methyl] propionate; LS 2265 (taurine derivative of fenofibrate); bezafibrate (2-(4-(2-[4-chlorobenzamido)ethyl] phenoxy)-methyl propionic acid; gemfibrozil (5-2[2,5-dimethylphenoxy]2-2-dimethylpentanoic acid); methyl clofenapate (methyl-2-[4-(p-chlorophenyl)phenoxy]-2-methyl propionate); DG 5685 (5-[4-phenoxybenzyl]trans-2-(3-pyridyl)1,3-dioxane); DH 6463 (5-[4-phenoxybenzyl] trans-2-(3-pyrimidinyl)-1,3-dioxane); tiadenol(bis[hydroxyethylthio]-7, 10-decane); ciprofibrate (2,-[4-(2,2-dichlorocyclopropyl)-phenoxy]2-methyl propionic acid) and RMI-14,514 ( [5-tetradecycloxy]-2-furancarboxylic acid), produced a marked but variable increase in the activities of peroxisomal enzymes catalase, carnitine acetyltransferase, heat-labile enoyl-CoA hydratase and the fatty acid beta-oxidation system and in the amount of polypeptide PPA-80 as demonstrated by SDS-polyacrylamide gel electrophoresis. The peptide map patterns of polypeptide PPA-80 in liver induced by these compounds were strikingly similar. The ultrastructural studies demonstrate that fenofibrate, ciprofibrate, LS 2265, DG 5685 and DH 6463 can induce proliferation of peroxisomes in liver cells of rats, and further confirm the previous reports of hepatic peroxisome proliferative activity of methyl clofenapate, tiadenol, bezafibrate, gemfibrozil and RMI-14514, as shown morphologically. Whether these structurally unrelated chemicals or their metabolite(s) directly activate the peroxisome specific genes to induce this multi-enzyme system or they exert their action on peroxisomes indirectly by causing fatty acid overload in hepatocytes remains to be elucidated. These chemicals offer a simple and reproducible means of stimulating peroxisomal enzymes in liver and should serve as useful tools, for evaluating the implications of hepatic peroxisome proliferation and in elucidating the mechanism of peroxisome proliferator-induced carcinogenesis.
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PMID:Evaluation of selected hypolipidemic agents for the induction of peroxisomal enzymes and peroxisome proliferation in the rat liver. 684 Jul 92

1 The effects of hypolipidemic drugs fenofibrate (isopropyl[4-(p-chlorobenzoyl)-2-phenoxy-2-methyl]propionate), pyrinixil (BR-931; [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide]), methyl clofenapate (2-methyl-2[4-(p-chlorophenyl)phenoxy] 2-methyl-propionate), and clofibrate (ethyl alpha-p-chloro-phenoxyisobutyrate) on plasma triglyceride levels, hepatic peroxisome proliferation and peroxisome-associated enzymes in hamsters were investigated. 2 Fenofibrate, pyrinixil and methyl clofenapate were administered in the diet at 0.2% level (w/w) for 6 weeks. Clofibrate was fed at 0.5% level. 3 Fenofibrate, pyrinixil and methyl clofenapate induced a marked proliferation of peroxisomes in hamster liver cells which was comparable to that observed in the rat and mouse liver, whereas the peroxisome proliferative effect of clofibrate was less pronounced. Peroxisomal fatty acid beta-oxidation system was found in the hamster liver and its activity was enhanced significantly by hypolipidemic drugs. The magnitude of induction of [1(-14)C]palmitoyl CoA oxidation, heat-labile enoyl-CoA hydratase and peroxisome proliferation-associated 80000 mol. wt. polypeptide in the hamster appeared to parallel the extent of peroxisome proliferation. 4 All four hypolipidemic compounds increased hepatic catalase and carnitine acetyltransferase activities and decreased plasma triglyceride levels in the hamster. The observed hepatic effects of hypolipidemic drugs in hamster are identical to those induced by peroxisome proliferators in the rat and mouse. 5 These observations suggest that hypolipidemic agents identified as peroxisome proliferators in rats, mice and now hamsters would very likely enhance the peroxisomal enzyme system in other species. Additional information on the interspecies responses to peroxisome proliferators, however, is necessary to assess the role of peroxisome proliferation in carcinogenesis.
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PMID:Induction of hamster hepatic peroxisomal beta-oxidation and peroxisome proliferation-associated 80000 mol. wt. polypeptide by hypolipidemic drugs. 717 94

The effects of phorbol ester tumor promoters and related compounds on superoxide dismutase (SOD) and catalase were examined. The treatment of adult mouse skin with 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a sustained decrease in the basal levels of both SOD and catalase activities in the epidermis. A decline in SOD activity occurred within 3 h after application and the maximum effect was seen at 16--17 h. The decrease in SOD activity was always accompanied by a similar decline in the epidermal catalase activity. The alterations in both enzymes occurred against a high background of enhanced protein synthesis which indicates that the effect of TPA is selective for SOD and catalase. Other tumor promoters such as phorbol 12,13-dibutyrate and the non-phorbol tumor promoter anthraline also lowered the activities of both the enzymes. Mezerein, a resiniferonol derivative with weak promoting activity but a potent stage-II promoter, appeared to be more potent than TPA in lowering the basal levels. These results indicate that damage which favors neoplastic progression could occur in TPA-treated mouse skin due to the accumulation of free radicals resulting from low levels of SOD and catalase activity. In addition, the TPA-caused decrease in the levels of SOD and catalase was not prevented by either retinoic acid, fluocinolone acetonide, tosyl amino-2-phenylethyl chloromethyl ketone, or butylated hydroxytoluene, suggesting that inhibition of tumor promotion by these agents is not mediated through alterations in the levels of enzymatic activities which decrease free radical concentrations.
Carcinogenesis 1981
PMID:Diminution of mouse epidermal superoxide dismutase and catalase activities by tumor promoters. 731 51

The authors have studied DNA base damage and activities of antioxidant enzymes in human benign prostatic hyperplasia (BPH) tissues and surrounding disease-free tissues removed from prostate glands of 15 patients. In these tissues, endogenous levels of various typical hydroxyl radical-induced products of DNA bases and activities of catalase and superoxide dismutase were measured. The majority of patients had higher levels of DNA base lesions and lower activities of enzymes in BPH tissues than in normal prostate tissues. When activities of both enzymes were lower in BPH tissues than in normal tissues, the increases in the amounts of DNA base lesions over control levels were most prominent. In the case of similar enzyme activities in both BPH and normal tissues, no changes in levels of DNA base lesions were observed. These results suggest a possible association between antioxidant enzyme activities and levels of DNA base lesions in BPH tissues. Some of the identified DNA lesions are known to be premutagenic and may play a role in carcinogenesis. Although a possible link between BPH and prostate cancer is controversial, BPH patients with both decreased antioxidant enzyme activities and increased levels of DNA lesions may be at risk of developing prostate cancer.
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PMID:DNA base modifications and antioxidant enzyme activities in human benign prostatic hyperplasia. 753 80

Incubation of chromium(VI) [Cr(VI)] with cultured Jurkat cells resulted in activation of DNA binding activity of the nuclear factor (NF)-kappa B. In a combination with glutathione reductase, a Cr(VI) reducing agent, Cr(VI) expressed an enhanced activity in induction of NF-kappa B. This activation of NF-kappa B was decreased by a metal chelator, diethylene-triaminepentaacetic acid or catalase, but increased by superoxide dismutase. Addition of Mn2+, which reacts with Cr(IV) and inhibits Cr(IV)-mediated hydroxyl radical (.OH) generation via Fenton-like reaction, attenuated the activation of NF-kappa B. Sodium formate, an .OH radical scavenger, also inhibited the activation. Electron spin resonance measurements showed that the incubation of Cr(VI) with intact Jurkat cells generated reactive Cr(V) intermediate. Glutathione reductase and NADPH enhanced Cr(V) generation. Electron spin resonance spin trapping measurements using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent provided evidence that the incubation of Cr(VI) with the Jurkat cells in the presence of glutathione reductase generated .OH radicals. H2O2 enhanced .OH radical generation and also enhanced Cr(V) formation, indicating the role of Cr(IV) in .OH radical generation. We conclude that Cr(VI) can activate NF-kappa B in vitro via Cr(IV)-mediated free radical reactions. We hypothesize that Cr(VI)-mediated NF-kappa B activation may be involved in the mechanism of Cr(VI)-induced carcinogenicity.
Carcinogenesis 1995 Oct
PMID:Chromium(VI)-induced nuclear factor-kappa B activation in intact cells via free radical reactions. 758 42

DNA cleavage induced by metallothionein (MT) containing copper was investigated by a DNA sequencing technique. Reconstituted Cd7-MT showed no ability to cause DNA cleavage. Commercially available rabbit MT I caused DNA cleavage, suggesting that DNA cleavage is due to the metal contained in commercial Mt. Cu2Cd5-MT and Cu12-MT were prepared by the treatment of commercial rabbit MT I with [Cu(CH3CN)4]CIO4. Cu12-MT frequently induced an alteration of thymine residues, especially in the 5'-GTC-3' sequence, and piperidine treatment led to chain cleavage at the thymine residues. The site specificity was similar to that obtained with Cu(I) plus H2O2. H2O2 enhanced DNA cleavage induced by Cu12-MT. Catalase and a Cu(I)-specific chelating agent, bathocuproine, inhibited DNA cleavage. These results suggest that Cu(I) and H2O2 have important roles in the production of active species causing DNA cleavage. Commercial MT and Cu2Cd5-MT induced DNA cleavage much less than Cu12-MT, but gave particularly specific DNA cleavage. Cu2Cd5-MT induced cleavage specifically at the central guanine residue of the 5'-GGT-3' sequence. A similar cleavage pattern was obtained with commercial MT. No effect of piperidine treatment suggests that the DNA cleavage might not be due to base damage and/or liberation. The DNA cleavage was inhibited efficiently by EDTA, but not by bathocuproine and catalase. Experiments with DNA ligands, albumin, and denatured DNA suggest that commercial MT and Cu2Cd5-MT induce nonoxidative cleavage of the deoxyribose phosphate backbone through its DNA recognition. These two types of cleavage mechanisms are discussed in relation to the possible role of Cu-MT in carcinogenesis.
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PMID:Oxidative and nonoxidative mechanisms of site-specific DNA cleavage induced by copper-containing metallothioneins. 761 16

Recent studies from this laboratory have shown that asbestos fibers are mutagenic in cultured mammalian cells when assayed using a system that can detect multilocus deletions. Southern analysis of the induced mutants shows that the majority contain large deletions ranging in size from a few thousand to several million basepairs. In the present study, the effects of free radical scavenging enzymes on the cytotoxic and mutagenic potential of chrysotile fibers were examined using the human-hamster hybrid (AL) cells. Exponentially growing cells were treated with graded doses of fibers for a 24 h period either in the presence or absence of catalase, superoxide dismutase (SOD) or Tempol. Fiber-exposed cells were treated with the various enzymes either concurrently with the fiber or extended through the entire expression period. While the survival of AL cells treated with graded doses of chrysotile fibers with or without a concurrent treatment with SOD and catalase was not significantly different, the mutation yield at the S1 locus was significantly reduced in cells treated with these antioxidant enzymes. Furthermore, cells treated with the enzymes for a prolonged period were not better protected than those treated only during fiber treatment. The SOD mimic nitroxide, Tempol, had no effect on either the survival or mutagenic yield of chrysotile fibers. While SOD and catalase reduced the mutagenic potency of asbestos fibers in AL cells, they did not alter the molecular spectrum of fiber-induced mutagenesis. Our results indicate that antioxidant enzymes can protect cells against the genotoxic damages induced by chrysotile fibers, and are highly suggestive of the roles of oxyradicals in the fibrogenic and carcinogenic mechanisms of asbestos fibers.
Carcinogenesis 1995 Jul
PMID:Effects of antioxidants on fiber mutagenesis. 761 91

In this work comprehensive data of antioxidant enzymes are reviewed and their role in carcinogenesis is discussed. When compared to their normal tissue counterparts, more of the tumor tissues were low in Cu, Zn-SOD and catalase activity and in some cases in Mn-SOD. It is probably characteristic for tumor tissues. Glutathione peroxidase, and glutathione reductase and glucose-6-phosphate dehydrogenase activities are highly variable. The reason why cancerous cells exhibit abnormal levels and activities of antioxidant enzymes is unknown. It was hypothesized, that during formation of the tumor, by certain obscure mechanism, cells with imbalance of antioxidant enzymes profile were selected over normal cells. It is not known whether the changes in antioxidant defence observed in cancerous tissues play a role in carcinogenesis, or are formed as a results of the disease.
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PMID:[Activity of antioxidant enzymes in cancer diseases]. 763 95

In recent years, more attention has been given to the mechanism of disease induction caused by the surface properties of minerals. In this respect, specific research needs to be focused on the biologic interactions of oxygen radicals generated by mineral particles resulting in cell injury and DNA damage leading to fibrogenesis and carcinogenesis. In this investigation, we used electron spin resonance (ESR) and spin trapping to study oxygen radical generation from aqueous suspensions of freshly fractured crystalline silica. Hydroxyl radical (.OH), superoxide radical (O2.-) and singlet oxygen (1O2) were all detected. Superoxide dismutase (SOD) partially inhibited .OH yield, whereas catalase abolished .OH generation. H2O2 enhanced .OH generation while deferoxamine inhibited it, indicating that .OH is generated via a Haber-Weiss type reaction. These spin trapping measurements provide the first evidence that aqueous suspensions of silica particles generate O2.- and 1O2. Oxygen consumption measurements indicate that freshly fractured silica uses molecular oxygen to generate O2.- and 1O2. Electrophoretic assays of in vitro DNA strand breakages showed that freshly fractured silica induced DNA strand breakage, which was inhibited by catalase and enhanced by H2O2. In an argon atmosphere, DNA damage was suppressed, showing that molecular oxygen is required for the silica-induced DNA damage. Incubation of freshly fractured silica with linoleic acid generated linoleic acid-derived free radicals and caused dose-dependent lipid peroxidation as measured by ESR spin trapping and malondialdehyde formation. SOD, catalase, and sodium benzoate inhibited lipid peroxidation by 49, 52, and 75%, respectively, again showing the role of oxygen radicals in silica-induced lipid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Silica radical-induced DNA damage and lipid peroxidation. 770 89

The generation of 8-hydroxydeoxyguanosine (8OHdG) in calf thymus DNA treated with O-phenylphenol (OPP) or its major metabolites, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), was studied. The content of 8OHdG residues was increased in DNA treated with PHQ, and the generation of 8OHdG was highly dependent on PHQ concentration. PBQ had little effect on the formation of 8OHdG, and OPP had no effect. The formation of 8OHdG by PHQ was reduced by oxygen radical scavengers such as catalase, sodium benzoate and sodium azide. The PHQ-induced 8OHdG formation was accelerated by the addition of CuCl or CuCl2 to the reaction mixture, but was decreased by the addition of chelating agents such as EDTA, bathocuproinedisulfonic acid disodium salt (bathocuproine disulfonate) and O-phenanthroline. These results demonstrate that hydroxyl radicals generated in the process of oxidation of PHQ contribute to the formation of 8OHdG in DNA, and copper ions facilitate the oxidative DNA damage. Copper ions greatly accelerated the PHQ-induced DNA cleavage in vitro, although they had no effect on cleavage without PHQ. On the other hand, DNA cleavage occurred by the addition of FeCl2 in the absence and presence of PHQ. FeCl2 stimulates 8OHdG formation only slightly with or without PHQ. Furthermore, the stimulatory effect of FeCl2 on 8OHdG formation was observed even in the presence of EDTA. The formation of 8OHdG in bladder DNA is likely to be one of a series of events leading to bladder tumors seen in rats fed OPP-containing diet.
Carcinogenesis 1995 Apr
PMID:Formation of 8-hydroxydeoxyguanosine in calf thymus DNA treated in vitro with phenylhydroquinone, the major metabolite of O-phenylphenol. 772 64


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