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

Rats were fed the peroxisome proliferator ciprofibrate (0.025%), and the effects on the expression, modification, and localization of seven domain-specific integral proteins of the rat hepatocyte plasma membrane were assessed using a combination of immunoblotting, -precipitation, and -fluorescence. Ciprofibrate caused the down-regulation of five of the plasma membrane proteins (the epidermal growth factor receptor, the asialoglycoprotein receptor, HA 321, HA 4, and dipeptidylpeptidase IV) and induced the expression of a more basic, lower-Mr isoform of the basolateral plasma membrane protein CE 9. Pulse labeling, chemical deglycosylation, and 125I-wheat germ lectin blotting suggested that the ciprofibrate-induced isoform of CE 9 differed in the posttranslational modification of its oligosaccharides and contained more sialic acid. These changes in hepatocyte surface differentiation were first observed between Days 1 and 5 on the ciprofibrate-containing diet, coincident with other aspects of the pleiotropic response of the hepatocyte to peroxisome proliferators, e.g., the induction of the Mr 78,000 peroxisome proliferation-associated protein. The effects were reversed within 2-3 weeks upon removal of ciprofibrate. The three other peroxisome proliferators tested, di(2-ethylhexyl)phthalate, clofibrate, and Wy-14,643, were found to exert most of these same effects on the expression and modification of the hepatocyte plasma membrane proteins, but the compounds differed in relative potency. The ciprofibrate-induced decreases in the concentrations of the epidermal growth factor receptor, the asialoglycoprotein receptor, HA 321, and HA 4 were similar to the selective down-regulation of these proteins observed transiently during the period of hepatocyte proliferation following two-thirds hepatectomy. Other compounds frequently used in studies of liver enzyme induction and carcinogenesis, the antioxidants ethoxyquin and butylated hydroxyanisole and the liver tumor promoter phenobarbital, were not as effective as ciprofibrate or two-thirds hepatectomy at causing the down-regulation of these proteins. The induction of the lower-Mr isoform of the basolateral plasma membrane protein CE 9 was not observed following two-thirds hepatectomy or upon the feeding of the antioxidants or phenobarbital but was specific to the feeding of the peroxisome proliferators.
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PMID:Peroxisome proliferator-induced alterations in the expression and modification of rat hepatocyte plasma membrane proteins. 240 74

To determine if the carcinogenic potential of peroxisome proliferators is dependent upon their ability to induce cell proliferation, we have investigated the extent of cell proliferation in the livers of rats fed ciprofibrate, a peroxisome proliferator. Male rats were maintained on a diet containing ciprofibrate (0.025% w/w) and killed at selected intervals following 1 week of continuous [3H]thymidine labeling. Evaluation of labeling indices demonstrated a significant increase in cell proliferation during the first week but not in rats killed at the end of 5 and 20 weeks of treatment. Increases in hepatocyte nuclear labeling were found at 40 and 70 weeks of ciprofibrate administration which coincided with the appearance in livers of putative preneoplastic and neoplastic lesions. In a short-term feeding study, ciprofibrate and ethoxyquin were fed to rats at a dietary concentration of 0.025% and 0.5%, respectively, either alone or in combination for 7 days. Ciprofibrate and ethoxyquin either alone or in combination produced marked hepatomegaly and a significant increase in DNA synthesis as demonstrated by [3H]thymidine incorporation and autoradiographic studies. DNA synthesis in the group receiving ciprofibrate and ethoxyquin simultaneously, was slightly more than in animals that received either compound alone, suggesting a synergistic effect, although chronic feeding of these agents together resulted in inhibition of liver carcinogenesis (Rao, M. S. et al. (1984) Cancer Res., 44, 1072-1076). The results of this study further suggest that cell proliferation induced by peroxisome proliferators may be less important in carcinogenesis than peroxisome proliferation induced by these compounds.
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PMID:Evaluation of liver cell proliferation during ciprofibrate-induced hepatocarcinogenesis. 263 30

Previous studies from our laboratories have shown that carcinogenic peroxisome proliferators significantly increase the mRNA levels of peroxisomal beta-oxidation genes in the rat liver by enhancing the transcriptional activity. Because of a good correlation between the inducibility of peroxisome proliferation and carcinogenicity of this class of xenobiotics, we proposed that sustained induction of peroxisomal beta-oxidation system and the resultant oxidative stress form the basis for carcinogenesis. Since this concept implies that tumors should develop only in tissues which display maximal peroxisome proliferation, we have now assessed the degree to which catalase and the three beta-oxidation genes are expressed in liver and 12 extrahepatic tissues of adult rats fed for 2 weeks a diet containing 0.025% ciprofibrate (w/w), a peroxisome proliferator. In the ciprofibrate-treated rats, the levels of catalase mRNA increased to less than 2-fold in liver, kidney, intestine, and heart, but no change was detected in other tissues. The mRNA levels of the three genes of beta-oxidation system in the liver of adult rats treated with ciprofibrate increased greater than 20-fold. In contrast, in the kidney, small intestine, and heart the increases in the mRNA levels of all three beta-oxidation genes were small and varied from 2- to 4-fold following ciprofibrate treatment. Ciprofibrate did not significantly increase the levels of these mRNAs in the other nine tissues. These results correlated well with the levels of peroxisomal beta-oxidation activity, peroxisome volume density, and the immunologically quantified proteins in various tissues. These results provide evidence for the presence of beta-oxidation enzymes in peroxisomes of many tissues of rat and for tissue (cell)-specific differences in the inducibility of mRNAs of these beta-oxidation genes. The marked inducibility of beta-oxidation genes in liver and subsequent development of liver tumors support the hypothesis that tumors develop in tissues that show inducibility of peroxisome proliferation vis a vis beta-oxidation system following exposure to peroxisome proliferators.
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PMID:Comparison of constitutive and inducible levels of expression of peroxisomal beta-oxidation and catalase genes in liver and extrahepatic tissues of rat. 290 Jun 80

To understand the mechanism of peroxisome proliferator-induced oxidative stress in non-mutagenic carcinogenesis, the effect of ciprofibrate, a peroxisome proliferator, on the activities and protein amounts of various antioxidant enzymes in different subcellular compartments was examined. Ciprofibrate treatment for short-term (3 weeks) as well as long-term (12 weeks) duration increased the total cellular catalase activity, whereas superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities were decreased significantly. Withdrawal of ciprofibrate from the diet did not normalize these activities. The observed decreases in total cellular SOD and GPX activities following ciprofibrate treatment were due to significant decreases in cytosolic CuZn SOD and GPX, whereas mitochondrial levels of Mn SOD and GPX were relatively unchanged. The peroxisomal CuZn SOD and GPX activities were increased significantly after both short- and long-term treatment, whereas catalase activity was reduced. Western blot analysis of cytoplasm for GPX and CuZn SOD showed a significant decrease in GPX and CuZn SOD proteins. Mitochondrial GPX protein was found to be slightly decreased, whereas Mn SOD protein levels did not show any significant change. The excessive production of H2O2 by oxidases and O2- by the cytochrome P450 enzyme system, along with the observed loss of antioxidant protection by loss of activities of catalase in peroxisomes and GPX and CuZn SOD in cytoplasm, may be the critical factors in peroxisomal proliferator-induced oxidative stress and initiation and promotion of carcinogenesis by this class of non-mutagenic agents. Both enzyme activities, as well as protein amounts of GPX and CuZn SOD, were higher in peroxisomes but lower in cytoplasm in ciprofibrate-treated liver as compared to control liver. The Mn SOD protein was decreased in peroxisomes, whereas mitochondrial Mn SOD was relatively unaffected in ciprofibrate-treated liver as compared to control. These observations suggest that the regulation of expression of peroxisomal CuZn SOD and Mn SOD is different from their counterparts in other cellular compartments.
Carcinogenesis 1994 Sep
PMID:Antioxidant enzymes in ciprofibrate-induced oxidative stress. 792 86

The objective of this study was to compare the effects of perfluorodecanoic acid (PFDA) and ciprofibrate on the induction of hepatic toxicity and on hepatocellular proliferation in rats. In the first study, rats were first subjected to partial hepatectomy and then injected with [3H]thymidine (20 microCi/injection) at 23, 24, 25, 47, 48 and 49 h afterwards. After a 2 week recovery period, rats were injected with one of four levels of PFDA (0.3, 1.0, 3.0 or 10 mg/kg/injection) in four i.p. doses every 14 days, or were fed 0.01% or 0.003% ciprofibrate. Six days after the last PFDA injection and three days before the animals were killed, an osmotic minipump containing 20 mg/ml 5-bromo-2'-deoxyuridine (BrdU) was implanted s.c. for the measurement of DNA synthesis. Peroxisomal fatty acyl-CoA oxidase activity was significantly enhanced in both PFDA and ciprofibrate-treated groups in a dose-dependent manner. Hepatotoxicity, measured as the loss of [3H]thymidine from hepatic DNA, was not significantly affected by any of the treatments. Hepatic DNA synthesis was significantly increased only in rats receiving the highest dose of PFDA. In order to determine the time course of ciprofibrate- and PFDA-induced cell proliferation, we conducted another study with more time points. Rats were fed 0.01% ciprofibrate or were injected every 14 days with 3 or 10 mg PFDA/kg body weight for 10 days, 24 days, 6 weeks, 26 weeks or 54 weeks. Cell proliferation was quantified as in the first study. Ciprofibrate increased cell proliferation at the early but not the later time points, whereas PFDA increased cell proliferation at most times throughout the study. This study demonstrates that PFDA and ciprofibrate do not selectively induce hepatic toxicity and that their effects on cell proliferation do not correlate with their carcinogenic or promoting activities.
Carcinogenesis 1994 Dec
PMID:Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cell proliferation and toxicity in Sprague-Dawley rats. 800 Dec 45

The ECL-cell hyperplasia and ECL-cell carcinoids occurring during long-term treatment with ciprofibrate, have been attributed to hypergastrinemia secondary to an inhibitory effect on acid secretion. However, nobody has given any explanation of the mechanism by which ciprofibrate and related phenoxyisobutyrate derivates inhibit acid secretion. Moreover, the reported inhibition of acid secretion has only been moderate, in contrast to the profound inhibition of acid secretion needed to induce similar ECL-cell changes. To re-examine the effect of ciprofibrate on gastric acidity and serum gastrin, we randomly assigned 33 male Fisher rats into three treatment groups (100 or 20 mg/kg/day of ciprofibrate and control) during a period of 4 weeks. Daily assessments of gastric acidity was done by gastric intubation, using a tube with a diameter of 2.0 mm allowing the introduction of an infant pH-catheter. Measurements were done in all animals 5 days a week. Ciprofibrate did not raise gastric pH. On the contrary, the highest dose increased the acidity. Serum gastrin levels measured in blood taken by vein puncture before the initiation of the drug treatment and on the last day of the 4 week treatment period, revealed a dose-related significant hypergastrinemic effect of ciprofibrate. The slight increase in gastric acidity in the ciprofibrate high-dose group is most likely due to the hypergastrinemia provoked by the drug. This hypergastrinemia is therefore not secondary to an inhibition of acid secretion, but may be due to a direct effect of ciprofibrate on the G-cell. The ECL-cell hyperplasia and the ECL-cell carcinoids, which develop during treatment with peroxysome-proliferators are thus due to hypergastrinemia, which is not secondary to inhibition of acid secretion.
Carcinogenesis 1996 Oct
PMID:The peroxisome-proliferator ciprofibrate induces hypergastrinemia without raising gastric pH. 889 82

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

Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-alpha (PPARalpha), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPARalpha agonist-responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate-dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate-dosed rats, and some of these are potential targets of PPARalpha. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.
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PMID:Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-alpha agonist ciprofibrate. 1285 64

Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands evoke a profound mitogenic response in rodent liver, and the aim of this study was to characterize the kinetics of induction of DNA synthesis. The CAR ligand, 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene, caused induction of hepatocyte DNA synthesis within 48 h in 129S4/SvJae mice, but the potent PPARalpha ligand, ciprofibrate, induced hepatocyte DNA synthesis only after 3 or 4 days dosing; higher or lower doses did not hasten the DNA synthesis response. This contrasted with the rapid induction (24 h) reported by Styles et al., 1988, Carcinogenesis 9, 1647-1655. C57BL/6 and DBA/2J mice showed significant induction of DNA synthesis after 4, but not 2, days ciprofibrate treatment. Alderley Park and 129S4/SvJae mice dosed with methylclofenapate induced hepatocyte DNA synthesis at 4, but not 2, days after dosing and proved that inconsistency with prior work was not due to a difference in mouse strain or PPARalpha ligand. Ciprofibrate-induced liver DNA synthesis and growth was absent in PPARalpha-null mice and are PPARalpha dependent. In the Fisher344 rat, hepatocyte DNA synthesis was induced at 24 h after dosing, with a second peak at 48 h. Lobular localization of hepatocyte DNA synthesis showed preferential periportal induction of DNA synthesis in rat but panlobular zonation of hepatocyte DNA synthesis in mouse. These results characterize a markedly later hepatic induction of panlobular DNA synthesis by PPARalpha ligands in mouse, compared to rapid induction of periportal DNA synthesis in rat.
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PMID:Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPARalpha. 1837 45


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