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)

An increasing number of chemicals that produce tumours in rodent bioassays belong to the non-genotoxic class of carcinogens. There are no suitable tests for these carcinogens and our understanding of their mechanism of action is poor. Importantly, assessment of their potential hazard to man is usually difficult without extensive research. Peroxisome proliferators (PP) are a diverse group of rodent non-genotoxic carcinogens that include hypolipidemic drugs, plasticizers and herbicides. We have reported previously the cloning of a member of the nuclear hormone receptor superfamily and, through the use of chimeric receptors, discovered that it could be activated by PPs. The receptor is therefore termed the PP activated receptor (PPAR). The most widely used marker of PP action is the peroxisomal beta-oxidation enzyme acyl CoA oxidase (ACO). Interestingly, it has been speculated that the hydrogen peroxide produced as a result of ACO activity could lead to DNA damage and tumorigenesis. We have now demonstrated that PPAR recognizes a specific PP response element (PPRE) located in the ACO gene promoter and that the response is dependent upon the presence of receptor and the addition of the PP Wy-14,643. These data therefore support a model in which the mechanism of PP action is mediated by PPAR in a manner similar to that of steroid hormone action. Learning more about the function of PPAR offers a unique opportunity to understand the mechanism of action of some non-genotoxic carcinogens. Furthermore, this knowledge when combined with comparison of receptor expression between rodents and man will be important in providing a framework for a new threshold model of risk assessment based upon receptor-mediated carcinogenesis.
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PMID:The molecular mechanism of peroxisome proliferator action: a model for species differences and mechanistic risk assessment. 133 74

An important feature of malignant transformation is loss of the cholesterol feedback inhibition mechanism that regulates cholesterol synthesis. Cancer cells seem to require an increase in the concentrations of cholesterol and of cholesterol precursors. Therefore, a reasonable assumption is that prevention of tumour-cell growth can be achieved by restricting either cholesterol availability or cholesterol synthesis. In-vivo and cell-culture experiments have shown that lowering the plasma cholesterol concentration or intervening in the mevalonate pathway with 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors decreases tumour growth. Currently prescribed doses of HMG-CoA reductase inhibitors given orally or continuously by an implantable infusion pump could achieve tumour therapeutic tissue concentrations of these agents. My hypothesis is that cholesterol inhibition can inhibit tumour cell growth, can act as an adjuvant to cancer chemotherapy, and, possibly, can prevent carcinogenesis.
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PMID:Cholesterol inhibition, cancer, and chemotherapy. 135 10

Immunohistochemical staining of enoyl CoA hydratase (ECH), a key peroxisomal enzyme, revealed that the putative preneoplastic lesions induced in livers by administration of the peroxisome proliferator (PP) clofibrate (0.3% in diet) to rats for 60 weeks or more, lacked this enzyme so that they could be detected as ECH-negative foci. ECH and other peroxisomal enzymes such as acyl CoA oxidase, catalase and carnitine-dependent acetyltransferase were also either not or only weakly expressed in most hepatic hyperplastic nodules and hepatomas induced by ciprofibrate (0.025% in diet), Wy-14,643 (0.1%) or BR-931 (0.2%), while being strongly induced in surrounding hepatocytes. These results indicate that the expression of ECH and other peroxisomal enzymes is repressed in putative preneoplastic and neoplastic lesions induced by PPs in rat livers and that these peroxisomal enzymes might therefore be used as negative markers.
Carcinogenesis 1992 Feb
PMID:Loss of peroxisomal enzyme expression in preneoplastic and neoplastic lesions induced by peroxisome proliferators in rat livers. 174 18

Two forms of cytosolic acetyltransferases, AT-I and AT-II, have been purified from hamster livers, and a comparison made of their chemical and catalytic properties and genetically expressed difference. Homogeneous AT-I and AT-II were 31 and 30 kd respectively on SDS-PAGE and catalyzed efficiently various N- and O-acetylations in their reconstitution systems. AT-I used both acetyl CoA and arylhydroxamic acids as acetyl donors, while AT-II did not utilize arylhydroxamic acids as acetyl donors. In the reconstitution system, purified AT-I, but not AT-II, catalyzed acetyl CoA-dependent O-acetylation of 2-N-hydroxyamino-6-methyldipyrido[1,2-alpha:3', 2'-d]imidazole (N-OH-Glu-P-1) and arylhydroxamic acid-dependent N-acetylation of 4-aminoazobenzene (AAB). On the other hand purified AT-II showed high activities of acetyl CoA-dependent N-acetylation of 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). Polyclonal antibodies raised against AT-I inhibited cytosolic acetylations of N-OH-Glu-P-1 and AAB, and to a lesser extent of AF, while PABA N-acetylation was only marginally inhibited. Using Western blots, both AT-I and AT-II were recognized by the antibodies. AT-I was detectable in all the livers examined, and the content did not differ among the individuals (monomorphic distribution). In contrast, AT-II was distributed polymorphically, and the trimodal distribution of AT-II (high, intermediate and low) was correlated with the phenotype identified by cytosolic N-acetylations of AF and PABA (rapid, intermediate and slow). In addition, cross-mating experiments with intra- and inter-phenotype animals confirmed that hepatic AT-II isozyme is inherited by a Mendelian co-dominant trait. These results indicate that the polymorphic appearance of an acetyltransferase, AT-II, is responsible for the N-acetylation polymorphism in individual hamsters.
Carcinogenesis 1990 Dec
PMID:Monomorphic and polymorphic isozymes of arylamine N-acetyltransferases in hamster liver: purification of the isozymes and genetic basis of N-acetylation polymorphism. 226 66

Peroxisome proliferators have been suggested to induce liver carcinogenesis as a result of increased peroxisomal hydrogen peroxide production and cellular oxidative stress. Primary monolayer cultures of hepatocytes isolated from male F344 rats were incubated in medium containing one of three different peroxisome proliferators and examined for the induction of peroxisomal CoA oxidase activity and lipid peroxidation. The latter parameter was determined by measuring levels of conjugated dienes in lipid fractions extracted from harvested cells. The peroxisome proliferators used in these studies were nafenopin and clofibric acid (two hypolipidemic drugs) and mono(2-ethylhexyl)phthalate (MEHP), the primary metabolite of the industrial plasticizer, di(2-ethylhexyl)phthalate (DEHP). The relative specific activity of peroxisomal acyl CoA oxidase was increased by about 300% after incubation for 44 h with 200 microM nafenopin; lower levels of induction were observed with clofibric acid or MEHP. Relative to controls, the level of conjugated dienes was increased approximately 2-fold after incubation with 200 microM nafenopin; there was no apparent increase in conjugated dienes after incubation with up to 200 microM MEHP or 400 microM clofibric acid. The increase in conjugated dienes with 200 microM nafenopin was inhibited by co-incubation with the antioxidant, N,N'-diphenyl-p-phenylenediamine. Thus, peroxisomal enzyme induction by nafenopin can result in membrane lipid peroxidation and monolayer cultures of rat hepatocytes may provide a useful model system for studying relationships between peroxisome proliferation, enhanced hydrogen peroxide production and cellular changes due to hepatic oxidative stress.
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PMID:Induction of peroxisomal acyl CoA oxidase activity and lipid peroxidation in primary rat hepatocyte cultures. 227 69

Squamous cell carcinomas were induced in hairless mice by repeated irradiations with UVB (280-320 nm, total dose 30 J/cm2) plus UVA (320-400 nm, total dose 168 J/cm2). The irradiated animals and non-irradiated controls were fed on diets with or without vitamin A supplementation (20,000 IU/kg). At the appearance of tumours, 30 to 43 weeks after the last irradiation, the vitamin A (retinol plus retinyl ester) concentrations in the serum, liver, epidermis and tumours and the retinol esterifying activities in microsomes from epidermis and tumours were measured. The liver and epidermal vitamin A concentrations were 2-3 times higher in vitamin A supplemented than in unsupplemented animals, but did not differ between tumour-bearing animals and non-irradiated controls receiving identical diets. The vitamin A concentration in the tumours was significantly lower than in perilesional epidermis. The largest difference (p less than 0.001) between the tumour and epidermal values was observed in the vitamin A supplemented group. The low vitamin A content of the tumours was entirely due to a marked (2 to 6-fold) reduction in the retinyl ester fraction. In contrast, the retinol content of the tumours was increased to twice that of normal epidermis. The activity of the esterifying enzyme, acyl-CoA:retinol acyltransferase (EC 2.3.1.76), was unchanged. The reason for the reduced retinyl ester concentration thus remains unclear. Still, it is possible that a disturbed interconversion of retinol to retinyl esters plays a role in murine photo-carcinogenesis.
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PMID:Decreased retinyl ester concentrations in UV-induced murine squamous cell carcinomas. 257 23

Enzyme activities related to fatty acid synthesis were determined in liver extracts of rats treated with thioacetamide (TAM) for 8 weeks. Lipogenesis and cholesterogenesis in vivo were evaluated both in liver and in epididymal adipose tissue. The enzymatic activities of ATP-citrate lyase, acetyl CoA carboxylase, fatty acid synthetase, glycerol kinase and NAD-kinase decrease progressively when TAM was chronically administered. However, in the same experimental conditions malic enzyme and other NADP-enzymes were noticeably increased. This increase can be related to an excess of NADPH production necessary for detoxification rather than for lipogenesis. The rate of in vivo incorporation of 3H2O into non-saponifiable fraction in liver showed an increase in the acute phase (1-3 days) of TAM-treatment. In the chronic phase of TAM intoxication this rate returned to values close to normality. The rate of in vivo incorporation of 3H2O to fatty acid fraction increased in the liver during the acute phase of TAM-treatment and showed a sharp decrease during the subacute and chronic phases of the intoxication. At the end of the 60-day period of TAM-treatment, the radioactivity incorporated into fatty acids was significantly lowered. These data showed that the alterations in hepatic lipogenesis observed during TAM administration are related to changes in the activities of lipogenic enzymes and probably are a consequence of alterations in plasma insulin concentration. Disturbances in lipid metabolism should play an important role in the pathogenesis of liver damage and its physiological significance could involve metabolic changes in proliferative and neoplastic liver diseases.
Carcinogenesis 1989 Mar
PMID:Lipogenesis and cholesterogenesis de novo in liver and adipose tissue. Alterations of lipid metabolism by the effect of short- and long-term thioacetamide administration to rats. 264 16

In mammalian hepatic cytosol both acetyltransferase and sulfotransferase are involved in the activation of N-hydroxy derivatives of arylamines and arylamides. The role of acetyltransferase is also shown in Salmonella, whereas no rigid evidence is provided on the role of sulfotransferase in Salmonella. In Ames mutagenesis test without S9-mix, the number of revertants of Salmonella typhimurium TA98 induced was 10-fold higher with 2-hydroxyamino-3-methylimidazo[4,5-f] quinoline (N-hydroxy-IQ) than with 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-hydroxy-Glu-P-1). The extents of the binding to calf thymus DNA of N-hydroxy-Glu-P-1 were, however, 3.9 to 8.6-fold higher than that of N-hydroxy-IQ in both acetyl CoA- and PAPS-fortified rat hepatic cytosol systems. To understand the mechanism causing the apparent discrepancy between the results of the mutation and DNA binding, the activating capacities of cytosols of S. typhimurium TA98 and TA98/1,8-DNP6 strains on the binding of N-hydroxy-Glu-P-1 and N-hydroxy-IQ have been examined in comparison with those of rat livers. Although both N-hydroxyarylamines were activated by hepatic cytosols in the presence of PAPS, no significant DNA binding of these N-hydroxyarylamines was detected in the presence of PAPS and either one of the two strains of bacterial cytosols. In addition, both cytosols of TA98 and TA98/1,8-DNP6 strains showed no measurable activity on the sulfation of p-nitrophenol, suggesting no capacity for sulfotransferase-mediated activation of N-hydroxyarylamines in Salmonella. On the contrary, the extents of the acetyl CoA-dependent binding of N-hydroxy-IQ in cytosols of TA98, but not of TA98/1,8-DNP6, were respectively 6- and 9-fold higher than those in hepatic cytosols of male and female rats, although the extents of the binding of N-hydroxy-Glu-P-1 were rather higher in hepatic than in bacterial cytosols. In addition, the covalent binding of N-hydroxy-2-acetylaminofluorene to DNA was detected in hepatic, but not in bacterial cytosols, although the binding of N-hydroxy-2-aminofluorene was detectable in both hepatic and bacterial cytosols in the presence of acetyl CoA. These results indicate that the metabolic activating capacities of Salmonella and rat liver cytosols differ qualitatively, and the difference in the substrate specificity of acetyltransferase between Salmonella and rat livers may be involved, in part, in the difference of their DNA damage in bacteria and mammals.
Carcinogenesis 1989 Sep
PMID:Enzymatic acetylation and sulfation of N-hydroxyarylamines in bacteria and rat livers. 267 Mar 4

N-Acetoxyarylamines are reactive metabolites that are implicated in the initiation of the carcinogenic process by some N-substituted aryl compounds. The objective of this study was to explore the relationship between the production of these reactive species and N-acetylation (NAT), a reaction previously demonstrated to be polymorphic in the human. Human liver and urinary bladder mucosa samples were frozen within 4-8 h post mortem. These tissues were assayed for the (i) O-acetylation (OAT) of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl (N-OH-DMABP) by acetyl CoA, (ii) intramolecular N,O-acetyltransfer (AHAT) of N-hydroxy-2-acetylaminofluorene (N-OH-AAF), (iii) NAT of 2-aminofluorene (2-AF) and p-aminobenzoic acid (PABA) by acetyl CoA and (iv) deacetylation of N-OH-AAF. Cytosolic AHAT and OAT showed partial inhibition by paraoxon. The ratio of paraoxon insensitive AHAT to OAT to NAT of PABA to NAT of 2-AF appears to be 1:2:11:22 using freshly made cytosols from frozen livers. Freezing of the cytosol resulted in extensive loss of activities. All four of these cytosolic enzyme activities exhibited a similar polymorphic response. Microsomal deacetylation showed a monomorphic response. Similar to the liver, urinary bladder epithelial cells also catalyzed the same reactions. However, the OAT and AHAT activities were detected mainly in microsomes. These data suggest that phenotypically rapid acetylators have a greater biochemical potential for the metabolic activation of aromatic amines by pathways that involve O-acetylation.
Carcinogenesis 1989 Apr
PMID:Metabolism of aromatic amines: relationships of N-acetylation, O-acetylation, N,O-acetyltransfer and deacetylation in human liver and urinary bladder. 270 22

Transplacental effect of cobalamin coenzyme, adenosylcobalamin (Adocbl), on the carcinogenic action of N-nitroso-N-ethylurea (ENU) was studied in culture of the mouse embryonic kidney tissue by histoautoradiography. Coenzyme methylmalonyl-CoA-mutase, Adocbl, injected into DBA/2 mice in the prenatal period did not stimulate the proliferative activity of epithelial cells of the embryonic kidney. The treatment with Adocbl did not intensify hyperplastic changes common for the early stages of carcinogenesis. The frequency of hyperplastic changes mainly of focal proliferation in kidney explants with the combined administration was considerably lower than with the isolated action of the carcinogen and amounted to 8.7% and 21.5%, respectively (P less than 0.001).
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PMID:[The modifying influence of adenosylcobalamin on the transplacental carcinogenic effect of N-nitroso-N-ethylurea in organ cultures of the kidneys of DBA/2 mice]. 275 37


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