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

Clofibrate, a peroxisome proliferator, is hepatocarcinogenic in rats in a dose-dependent fashion. While there is a relationship between peroxisome proliferation and rodent liver carcinogenesis, recent evidence also suggests an association between the tumorigenicity of peroxisome proliferators and sustained cell proliferation. To investigate the role of early cell proliferation in clofibrate-induced carcinogenesis and the predictive potential of this endpoint, in a 3-month study, rats were fed clofibrate doses equivalent to those used in the chronic bioassay, and cell proliferation was determined after 1 week and 3 months, using a 1-week continuous bromodeoxyuridine (BrdU)-labeling technique. Adult Sprague-Dawley rats were fed clofibrate at 1500, 4500, or 9000 ppm. Six rats/sex/group were killed after 1 or 13 weeks of treatment. Osmotic minipumps containing BrdU were implanted into rats 7 days prior to necropsy to determine the cumulative 7-day hepatocyte labeling index immunohistochemically. A dose-related increase in hepatocyte labeling index was seen after 1 week of treatment. However, at 13 weeks, sustained increases in hepatocyte proliferation were not seen; but a dose-related decrease in the hepatocyte labeling index was observed. Liver stereology at 13 weeks demonstrated a dose-related increase in liver weight and volume, but a decrease in hepatocyte nuclei per unit volume, a minimal increase or no change in the total number of hepatocyte nuclei per liver, and an absolute decline in the total number of BrdU-labeled hepatocyte nuclei per liver. These data suggest that in rats, clofibrate may influence hepatocarcinogenicity by decreases in normal hepatocyte proliferation over time and this effect may influence the pathogenesis of tumors at time points beyond 13 weeks of treatment.
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PMID:Studies of early hepatocellular proliferation and peroxisomal proliferation in Sprague-Dawley rats treated with tumorigenic doses of clofibrate. 152 55

The effects of clofibrate treatment on N-nitrosobis(2-hydroxypropyl)amine (BHP) induced liver, gall bladder, pancreas, lung and kidney carcinogenesis in hamsters were studied. Animals were given BHP as an initiator at a dose of 500 mg/kg body weight subcutaneously once a week for 5 weeks followed by diet containing 0.25 or 0.5% clofibrate for 30 weeks. Both doses of clofibrate promoted hepatocarcinogenesis as judged from the associated multiplicity of liver lesions including hyperplastic nodules and hepatocellular carcinomas. gamma-Glutamyltranspeptidase (gamma-GTP) activity was not expressed in those lesions in the liver of hamsters given BHP followed by a basal diet or diets containing clofibrate. Clofibrate at a dose of 0.5% in the diet, in contrast, inhibited the development of pancreatic adenocarcinomas and lung neoplasms, including adenomas and adenocarcinomas, without affecting carcinogenesis in the gall bladder and kidney. These results clearly indicate differential modification potential of clofibrate for BHP-induced liver, pancreas and lung carcinogenesis in Syrian hamsters.
Carcinogenesis 1988 Aug
PMID:Modulation of N-nitrosobis(2-hydroxypropyl)amine-induced carcinogenesis by clofibrate in hamsters. 340 39

An increase in cytosolic epoxide hydrolase (cEH) activity occurs in the livers of mice treated with peroxisome proliferating-hypolipidemic-nongenotoxic carcinogens. As increases in activity of epoxide metabolizing enzymes may reflect the carcinogenic mechanism, a detailed comparison of the response of cEH, microsomal epoxide hydrolase (mEH), and cytosolic glutathione S-transferase (cGST) activities using the geometrical isomers trans- and cis-stilbene oxide as substrates has been performed in livers from mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate]. The maximal increase of cEH activity occurred at lower dietary doses of clofibrate (0.5%) and within a shorter time (5 days) than mEH and cGST (2%, 14 days) activity. After 14 days at 0.5% clofibrate, cEH, mEH, and cGST activities were 250, 175, and 165% and 290, 220, and 75% of control values in male and female mice, respectively. Withdrawal of clofibrate from the diet resulted in a reversion of activities to control values within 7 days. Clofibrate treatment shifted the apparent subcellular compartmentation of all three enzymatic activities with an increase in the ratio of soluble to particulate activity. In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred. Both the increase of cEH activity and the appearance of mEH-like activity in the cytosol are novel responses of epoxide metabolizing enzymes, which may be related to the novel cellular responses that follow clofibrate treatment, peroxisome proliferation, hypolipidemia, and nongenotoxic carcinogenesis.
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PMID:Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate)), a peroxisome proliferator. 404 85

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

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

The Syrian hamster embryo (SHE) cell system was used to evaluate the ability of two hepatocarcinogenic structurally related peroxisome proliferators (PPs) to induce morphological transformation (MT) of SHE colonies and to inhibit gap junctional intercellular communication (GJIC). Clofibrate and methyl clofenapate (MCP), which was shown to be a more active PP and a more potent carcinogen in vivo than clofibrate, were compared. MCP appeared slightly more active in vitro than clofibrate in affecting MT and GJIC of SHE cells. The morphological transformation of SHE colonies was induced by 50 microM MCP, against 100 microM clofibrate. Moreover, 50 microM MCP potentiated the transforming effects of both benzo[a]pyrene and 12-O-tetradecanoylphorbol-13-acetate. The inhibition of GJIC, measured by transfer of lucifer yellow, was transient and occurred at concentrations inducing morphological transformation. MCP inhibited dye transfer at 50 microM and the inhibition lasted up to 24 h at 100 microM. Inhibition of communication lasted only 4 h with clofibrate and occurred at a higher concentration (175 microM). This study showed that both the SHE cell transformation and dye transfer assays were able to display the different activities of the two PPs, even though the difference in potency observed was smaller than in vivo. It also revealed interactions between non-genotoxic carcinogens and the ability of the SHE cell transformation assay to detect these combined effects.
Carcinogenesis 1997 Apr
PMID:Comparative effects of clofibrate and methyl clofenapate on morphological transformation and intercellular communication of Syrian hamster embryo cells. 911 Dec 3