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)

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are mutagenic and carcinogenic heterocyclic amines produced during the ordinary cooking of meat. These compounds undergo metabolic activation via both cytochrome P450-mediated N-oxidation and phase II esterification in order to exert their genotoxicity. In the current study, we examined the in vitro phase II activation of N-hydroxy-IQ, N-hydroxy-PhIP and N-hydroxy-MeIQx by cytosolic acetyltransferase, sulfotransferase, aminoacyl-tRNA synthetase and phosphatase from a number of tissues including liver, kidney, colon and heart. These tissues were chosen for study because each is either a target organ for carcinogenicity or has displayed high levels of DNA adducts in in vivo studies with the heterocyclic amines. Cytosol from various tissues of both monkeys and rats was incubated with and without the respective cofactors, and carcinogen binding to calf thymus DNA was measured by 32P-postlabeling analysis. Our results show that all four phase II enzymes may participate in the activation of the N-hydroxylamines. However, the degree of activation depends on the substrate, tissue and animal species. For example, in both monkeys and rats, the highest acetyl CoA-enhanced binding was observed with N-hydroxy-IQ and the lowest acetyl CoA-enhanced binding was observed with N-hydroxy-MeIQx. In contrast, no significant adenosine 3'-phosphate 5'-phosphosulfate-dependent activation of N-hydroxy-IQ was observed with monkey cytosol from liver, kidney, heart or colon but the sulfotransferase-mediated activation of N-hydroxy-PhIP was at least 10 times higher in all four tissues of monkeys than in rats. Prolylation appears important in the activation of all three N-hydroxylamines by rat liver and heart cytosol, whereas in monkeys, prolylation appears important in kidney cytosol. The differences observed in the phase II activation of heterocyclic amines may have implications for DNA adduct formation, toxicity and carcinogenicity.
Carcinogenesis 1993 Oct
PMID:Enzymatic phase II activation of the N-hydroxylamines of IQ, MeIQx and PhIP by various organs of monkeys and rats. 822 59

Intraperitoneally administered N-hydroxy-N-2-fluorenylbenzamide (N-OH-2-FBA) and N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) are carcinogenic for rat peritoneum. The potential of peritoneal serosa to activate these compounds via deacylations and acyl transfers was compared to that of liver. N-Deacylations of N-OH-2-FBA and N-OH-2-FAA to N-2-fluorenylhydroxylamine (N-OH-2-FA) were faster by liver than serosa and by microsomes than cytosols. N-Debenzoylations of N-OH-2-FBA were 73- to 123-fold faster than N-deacetylations of N-OH-2-FAA. The esters, N-benzoyloxy-2-FBA and N-acetoxy-2-FAA, were O- and N-deacylated to N-OH-2-FA by liver, and the benzoate by serosa. Inhibition by paraoxon of the above deacylations implicated a serine carboxylesterase. Liver and serosa cytosols catalyzed acetyl CoA-, but not benzoyl CoA-, dependent and iodoacetamide (IAA)-sensitive N-acylation of N-2-fluorenamine (2-FA), implicating an acetyltransferase. In hepatic microsomes this activity was IAA-insensitive and partially inhibited by paraoxon. Liver cytosol, but not microsomes, used N-OH-2-FAA as an acyl donor and neither used N-OH-2-FBA. Liver and serosa catalyzed binding to DNA of N-OH-2-[ring-3H]FBA which was paraoxon-sensitive and increased by acetyl CoA, but not benzoyl CoA. Binding to DNA of N-OH-2-[ring-3H]FAA catalyzed by cytosols was approximately 22-fold greater in liver than in serosa and was IAA-sensitive. Microsome-catalyzed binding of this compound in both tissues was increased approximately 2-fold by acetyl CoA. The results support a two-step activation of N-OH-2-FBA in the liver consisting of esterase-catalyzed N-debenzoylation to N-OH-2-FA and an acyltransferase-catalyzed O-acetylation to the putative electrophile N-acetoxy-2-FA. In the serosa, binding to DNA appears to be due to rapid N-debenzoylation to N-OH-2-FA, a fraction of which is O-acetylated. Whereas activation of N-OH-2-FAA by liver and serosa microsomes may also involve N-OH-2-FA and/or its O-acetate, activation by the cytosols is consistent with N,O-acetyltransfer of N-OH-2-FAA to yield N-acetoxy-2-FA. The study provides first evidence for activation of N-OH-2-FBA by rat liver and of both compounds by peritoneum in vitro.
Carcinogenesis 1994 Feb
PMID:Activation of the carcinogens N-hydroxy-N-2-fluorenylbenzamide and N-hydroxy-N-2-fluorenylacetamide via deacylations and acetyl transfers by rat peritoneal serosa and liver. 831 3

Peroxisome proliferators are well known to cause liver enlargement in rodents. In this investigation, we have examined the effect of acute (1 week) and chronic (26 week) exposure to the peroxisome proliferators methylclofenapate (MCP) and clofibric acid (CA), at 0.05 and 0.5% in the diet respectively, on hepatocyte replication in the Sprague-Dawley rat. Both compounds induced an early increase in hepatocyte replication, with a concomitant increase in peroxisome proliferation as assessed by induction of palmitoyl CoA oxidation. However, after 26 weeks of treatment, there was no difference in the labelling index (LI) of control and CA-treated rat livers, while in MCP-treated rats the LI was 5- to 6-fold above control. Palmitoyl CoA oxidation remained elevated in both treated groups at 26 weeks. Analysis of the slides by a 'zonal' scoring procedure demonstrated that the induced replication was predominantly periportal after 1 week of treatment with either compound. The number of 5-bromo-2'-deoxyuridine (BrdU)-positive hepatocyte nuclei per field in the periportal region increased approximately 4-fold after CA treatment and 7-fold after MCP treatment. There was no significant difference in the number of BrdU-positive nuclei per field in the centrilobular areas of control and treated rats after 1 week. After 26 weeks of treatment, periportal replication was still elevated in the MCP-treated animals (approximately 10-fold above control), but there was no difference in periportal replication between control and CA-treated rats. CA induced a significant reduction in the replication of centrilobular areas at 26 weeks, while there was no effect of MCP. In summary, these results demonstrate that the acute mitogenic effects of MCP and CA are predominantly periportal, and, in the case of MCP, the mitogenicity is sustained up to 26 weeks of treatment.
Carcinogenesis 1993 Jul
PMID:Comparison of the acute and chronic mitogenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver. 833 Mar 63

While glutathione S-transferase P form (GST-P), a reliable marker for preneoplastic lesions induced by mutagenic hepatocarcinogens, is generally not expressed in rat liver foci, hyperplastic nodules and hepatomas induced by peroxisome proliferators (PPs), such lesions can be detected due to their peroxisomal enzyme-negative nature. For comparative purposes we examined the inducibility of enoyl CoA hydratase (ECH), a key peroxisomal enzyme, in rat hepatic preneoplastic lesions induced by mutagenic carcinogens. Clofibrate (CF) was therefore administered for 2 or 4 weeks following performance of the Solt-Farber protocol using diethylnitrosamine and 2-acetylaminofluorene. Immunohistochemical examination revealed no or only very weak expression of ECH within the induced foci in clear contrast to the strong staining of surrounding parenchyma. ECH expression was thus diametrically opposed to that of GST-P which was found only in foci. Although ECH was completely lacking in GST-P-strongly positive foci, it was expressed in GST-P-negative hepatocytes inside some foci otherwise positive for GST-P. CF administration resulted in a significant decrease in the numbers and areas of foci exhibiting strongly positive or positive GST-P staining; this being reflected in a lowering of GST-P protein levels. Furthermore, in primary cultured rat hepatocytes, clofibric acid as well as dexamethasone suppressed the expression of both GST-P and the oncogene, c-jun. These results taken together suggest that possible interaction of the PP receptor with JUN might be involved in loss of ECH expression in GST-P-strongly positive foci.
Carcinogenesis 1993 Mar
PMID:Lack of peroxisomal enzyme inducibility in rat hepatic preneoplastic lesions induced by mutagenic carcinogens: contrasted expression of glutathione S-transferase P form and enoyl CoA hydratase. 845 14

Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.
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PMID:Wine as a biological fluid: history, production, and role in disease prevention. 929 95

Retinoids, metabolites and synthetic derivatives of vitamin A (retinol), have been shown to inhibit carcinogenesis in various epithelial tissues in animal model systems and to have clinical efficacy as chemotherapeutic agents against certain types of cancer, including squamous cell carcinomas (SCCs). We examined the metabolism of [3H]retinol in normal human cell strains and SCC lines from the oral cavity and skin, and we report here that the cultured normal human epithelial cell strains esterified [3H]retinol to a much greater extent than the SCC lines. Furthermore, microsomal extracts of normal cell strains (e.g., OKF4) exhibited about 7-fold more palmityl-CoA-dependent, phenylmethylsulfonyl fluoride-resistant retinol esterification activity than extracts from SCC lines (e.g., SCC25). The fact that the esteriflcation of retinol was phenylmethylsulfonyl fluoride resistant suggests that the enzyme acyl-CoA:retinol acyltransferase is involved. Culture of both the normal and SCC lines in the presence of 1 microM all-trans-retinoic acid (RA) for 48 h enhanced the formation of [3H]retinyl esters from [3H]retinol. All of the cell lines examined can also metabolize [3H]retinol to [3H]RA, [3H]14-hydroxy-4,14-retroretinol, [3H]retinaldehyde, and [3H]3,4-didehydroretinol, but this metabolism occurs to varying extents in different cell lines. Culture of the cells in the presence of RA for 48 h did not affect the subsequent metabolism of [3H]retinol to [3H]RA and [3H]14-hydroxy-4,14-retroretinol, but it did reduce the metabolism of [3H]retinol to [3H]3,4-didehydroretinol. When cultured for 6-10 h in the presence of nanomolar concentrations of exogenous [3H]retinol, both the normal and SCC lines had much higher intracellular [3H]retinol concentrations, in the micromolar range. No correlation was seen between CRABP II or CRBP I mRNA levels and the levels of either intracellular [3H]retinol or [3H]retinol metabolism in these lines. The reduced ability to esterify retinol in these tumor cells may result in inappropriate cell growth and the loss of normal differentiation responses because of the lack of a sufficient amount of internal retinol stored as retinyl esters.
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PMID:Metabolism of all-trans-retinol in normal human cell strains and squamous cell carcinoma (SCC) lines from the oral cavity and skin: reduced esterification of retinol in SCC lines. 942 73

Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens that have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have examined if hepatic catalase overexpression in peroxisome proliferator-treated mice influences the induction of cell proliferation or the activation of transcription factors involved in cell proliferation. Transgenic mice or non-transgenic littermates were fed either 0.01% ciprofibrate or a control diet for 21 days. Fatty acyl CoA oxidase activity was not significantly affected by catalase overexpression, although the ratio of fatty acyl CoA oxidase to catalase was significantly decreased in transgenic animals. The labeling index in hepatocytes was significantly increased by ciprofibrate in non-transgenic mice, but catalase overexpression significantly inhibited this increase. Ciprofibrate increased the activation of nuclear factor (NF)-kappaB in non-transgenic mice, but this increase was inhibited by catalase overexpression. Ciprofibrate also increased AP-1 activation, but catalase overexpression did not significantly inhibit this increase, although AP-1 activation was 40% lower in transgenic mice. These results support the hypothesis that active oxygen plays a role in the induction of cell proliferation by the peroxisome proliferator ciprofibrate and therefore may be important in the carcinogenicity of these agents.
Carcinogenesis 1998 Apr
PMID:Liver-specific catalase expression in transgenic mice inhibits NF-kappaB activation and DNA synthesis induced by the peroxisome proliferator ciprofibrate. 960 Mar 48

Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens which have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have produced a transgenic mouse line that has elevated catalase activity specifically in the liver. In this study, we have examined if catalase overexpression influences the induction of lipid peroxidation or oxidative DNA damage, two mechanisms which have been hypothesized to be important in the carcinogenesis by peroxisome proliferators. Transgenic mice or non-transgenic litter mates were fed either 0.01% ciprofibrate or a control diet for 21 days. The activities of fatty acyl CoA oxidase and lauric acid hydroxylase were not significantly affected by catalase overexpression, although the ratio of fatty acyl CoA oxidase to catalase was significantly decreased in transgenic animals. Hepatic lipid peroxidation was estimated by quantifying the concentrations of malondialdehyde and conjugated dienes. Ciprofibrate treatment did not affect either endpoint, but catalase overexpression increased the concentrations of malondialdehyde (in untreated mice only) and conjugated dienes (in both untreated and ciprofibrate-fed mice). Oxidative DNA damage was estimated by quantifying 8-hydroxydeoxyguanosine (8-OHdG) by high-performance liquid chromatography/electrochemical detection. Ciprofibrate treatment significantly increased hepatic 8-OHdG concentrations, in agreement with several previous studies, but catalase overexpression did not significantly affect them, although 8-OHdG concentrations were decreased 50% in untreated mice. These results imply that the metabolism of hydrogen peroxide by catalase is not an important factor in the development of hepatic lipid peroxidation. The decrease in hepatic 8-OHdG in untreated transgenic mice and the increase seen after ciprofibrate administration imply that hydrogen peroxide is important in the formation of 8-OHdG. While the lack of decreased 8-OHdG levels in ciprofibrate-treated transgenic mice does not support this conclusion, it is possible that catalase levels were not sufficiently high to affect this endpoint. Transgenic mice with higher hepatic catalase activities may be required to resolve this issue.
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PMID:Effect of the peroxisome proliferator ciprofibrate on lipid peroxidation and 8-hydroxydeoxyguanosine formation in transgenic mice with elevated hepatic catalase activity. 964 Dec 60

The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are unclear but are mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha). To determine the role of PPARalpha in the mechanisms of hepatocarcinogenesis, the effect of Wy-14,643 on expression patterns of acyl CoA oxidase (ACO) and proteins involved in cell proliferation in the PPARalpha-null mouse were evaluated. ACO, CDK-1, CDK-2, CDK-4, PCNA and c-myc proteins were significantly increased in wild-type mice fed Wy-14,643 for 5 weeks or 11 months, as compared with controls. This effect was not observed in Wy-14,643-treated PPARalpha-null mice. Expression patterns of cyclin B1, cyclin D, cyclin E and p53 were not different in any of the groups. mRNAs encoding CDK-1, CDK-4, cyclin D1 and c-myc were also increased in wild-type mice fed Wy-14,643 but not in PPARalpha-null mice. These results indicate that the increase in CDK-1, CDK-4 and c-myc may be caused by an increase in transcription that is mediated directly or indirectly by PPARalpha. Thus PPARalpha-dependent alterations in cell cycle regulatory proteins induced by peroxisome proliferators are likely to contribute to the hepatocarcinogenicity of peroxisome proliferators.
Carcinogenesis 1998 Nov
PMID:Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver. 985 14

Our previous studies demonstrated that inhibitors of arachidonate-phospholipid remodeling [i.e. the enzyme CoA-independent transacylase (CoA-IT)] decrease cell proliferation and induce apoptosis in neoplastic cells. The goal of the current study was to elucidate the molecular events associated with arachidonate-phospholipid remodeling that influence cell proliferation and survival. Initial experiments revealed the essential nature of cellular arachidonate to the signaling process by demonstrating that HL-60 cells depleted of arachidonate were more resistant to apoptosis induced by CoA-IT inhibition. In cells treated with CoA-IT inhibitors a marked increase in free arachidonic acid and AA-containing triglycerides were measured. TG enrichment was likely due to acylation of arachidonic acid into diglycerides and triglycerides via de novo glycerolipid biosynthesis. To determine the potential of free fatty acids to affect cell proliferation, HL-60 cells were incubated with varying concentrations of free fatty acids; exogenously provided 20-carbon polyunsaturated fatty acids caused a dose-dependent inhibition of cell proliferation, whereas oleic acid was without effect. Blocking 5-lipoxygenase or cyclooxygenases had no effect on the inhibition of cell proliferation induced by arachidonic acid or CoA-IT inhibitors. An increase in cell-associated ceramides (mainly in the 16:0-ceramide fraction) was measured in cells exposed to free arachidonic acid or to CoA-IT inhibitors. This study, in conjunction with other recent studies, suggests that perturbations in the control of cellular arachidonic acid levels affect cell proliferation and survival.
Carcinogenesis 1999 May
PMID:Perturbations in the control of cellular arachidonic acid levels block cell growth and induce apoptosis in HL-60 cells. 1033 91


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