Disease relevance of CCRIS 173

• 2-[4(2,2- Dichlorocyclopropyl )phenoxy]2-methyl propionic acid (ciprofibrate), a peroxisome proliferator , induced hepatocytes in the pancreas of adult male F-344 rats when added to their diet at a dosage of 10 mg/kg body weight for 60-72 wk [1].
• Transfection of this expression vector into rat hepatoma H4IIEC3 cells in the presence of ciprofibrate resulted in a 5- to 10-fold, cell type-specific increase in luciferase activity as compared to cells transfected in the absence of drug [2].
• When challenged with a PPARalpha ligand, such as ciprofibrate or Wy-14,643, the SRC-1(-/-) mice displayed typical pleiotropic responses, including hepatomegaly, peroxisome proliferation in hepatocytes, and increased mRNA and protein levels of genes that are regulated by PPARalpha [3].
• The PPAR alpha agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia [4].
• 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 [5].

High impact information on CCRIS 173

• Gene expression patterns in HCCs from Acox1(-/-) mice and in ciprofibrate-induced HCCs were least similar to those observed in human HCCs [6].
• Peroxisome proliferator-induced hepatocarcinogenesis: histochemical analysis of ciprofibrate-induced preneoplastic and neoplastic lesions for gamma-glutamyl transpeptidase activity [7].
• A significant increase in the volume density of peroxisomes, together with immunochemically detectable amounts of two peroxisome-associated enzymes, was observed in pancreas with hepatocytes of rats maintained on ciprofibrate [1].
• Here we report the identification of such a transcriptionally active PPAR alpha-interacting cofactor (PRIC) complex from rat liver nuclear extracts that interacts with full-length PPAR alpha in the presence of ciprofibrate, a synthetic ligand, and leukotriene B(4), a natural ligand [8].
• T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal beta-oxidation enzymes in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene fused to the coding region of luciferase [9].

Chemical compound and disease context of CCRIS 173

• We have shown that during augmentative hyperplasia caused by the tumor promoters alpha-hexachlorocyclohexane, phenobarbital and ciprofibrate, plasma levels of HGF also increase [10].
• Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days [11].
• The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat [12].
• Compared with the control subjects (2.91 +/- 0.35 g/l), fibrinogen levels before treatment were higher in patients with dyslipidemia treated with ciprofibrate (3.42 +/- 0.59 g/l, NS) and fenofibrate (3.65 +/- 1.10 g/l, p < 0.05) [13].
• The peroxisome proliferators Wy-14,643, BR-931, nafenopin and ciprofibrate were tested in the primary hepatocyte culture-unscheduled DNA synthesis assay and in the Ames Salmonella microsome mutagenicity assay [14].

Biological context of CCRIS 173

• Mouse and rat PPARs, as well as Xenopus PPAR alpha (xPPAR alpha) could induce expression of a reporter gene linked to the hydratase/dehydrogenase PPRE in the presence of the peroxisome proliferators ciprofibrate or Wy-14,643, whereas xPPAR beta and xPPAR gamma were ineffective [15].
• Inhibition of cell proliferation by ciprofibrate in glutathione S-transferase P1-1-positive rat hepatic hyperplastic nodules [16].
• 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 [17].
• 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 [17].
• The induction of immediate-early gene expression in immortalized mouse liver cells by the PPs Wy-14, 643, monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate suggested that they may be activating growth-regulatory signal transduction pathways [18].

Anatomical context of CCRIS 173

• Gel retardation analysis with nuclear extracts demonstrated that ciprofibrate-treated or untreated H4IIEC3 cells, but not HeLa cells or monkey kidney cells, contained sequence-specific DNA binding factors that interact with the PPRE [2].
• Characterization of ciprofibrate and clofibric acid as peroxisomal proliferators in primary cultures of rat hepatocytes [19].
• The volume density of peroxisomes in transplanted hepatocytes increased 9.2- and 5.3-fold, respectively, in ciprofibrate- and DEHP-fed rats, whereas the volume density of mitochondria remained essentially unchanged [20].
• 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 [17].
• 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 [21].

Associations of CCRIS 173 with other chemical compounds

• Young male F-344 rats transplanted with dissociated hepatocytes were fed either a control diet or a diet containing 0.025% ciprofibrate or 2% DEHP [22].
• Treatment of LDLR-deficient mice with ciprofibrate caused a marked decrease in plasma apoB-48-carrying IDL and LDL but at the same time caused a large accumulation of triglyceride-depleted apoB-100-carrying IDL and LDL, resulting in a significant increase in plasma cholesterol levels [23].
• The effects of ciprofibrate (100 mg/d) on apolipoprotein (apo)B- and apoAI-containing lipoprotein subclasses, cholesteryl ester (CE) transfer protein activity, and plasma high-density lipoprotein (HDL)-mediated cellular cholesterol efflux were evaluated in 10 patients displaying type IIB hyperlipidemia [24].
• 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) [25].
• LY171883 and its structural analogue, LY189585, as well as the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate, bezafibrate and WY14,643, displaced [3H]oleic acid binding to FABP [26].

Gene context of CCRIS 173

• After 150 days of treatment with ciprofibrate, consistent with the increased plasma accumulation of apoB-100-carrying IDL and LDL, the LDLR-deficient mice displayed severe atherosclerotic lesions in the aorta [23].
• Administration of dexamethasone to mice in combination with ciprofibrate produced expression of the acidic SBP2 at 23% of the control level and the basic SBP2 at 36%, a slightly moderated reduction compared with the decrease that occurred with ciprofibrate alone [27].
• MMP-9 was specifically induced in CBS -/+ mice and inhibited by CF treatment [28].
• The highest activation of LPL was obtained after treatment with 200 mg ciprofibrate/day [29].
• A modest, but statistically significant, increase in HL activity was found after 100 or 200 mg ciprofibrate treatment [29].

Analytical, diagnostic and therapeutic context of CCRIS 173

• In RH nodules the Ya subunit of glutathione-S-transferase B (GST-B) and the Yb subunit of GST-A were increased 2-4-fold as compared to normal liver or in replicating liver following a 70% partial hepatectomy, while in CP nodules the Yb subunit was unaltered and the Ya subunit increased 4-fold as compared to normal [30].
• Electrophoretic mobility shift assay analysis showed that ciprofibrate elicited a concentration-dependent increase in the binding of nuclear extracts from cells of rat (Morris) and human (HepG2) origin to an ACO-peroxisome proliferator response element probe, although in HepG2 cells the increase was of marginal statistical significance [31].
• Human HepG2 and rat Fao hepatic-derived cell lines show different responses to ciprofibrate, a peroxisome proliferator: analysis by flow cytometry [32].
• Here we report that mRNA for alpha 2u-globulin, a rodent male specific protein, is markedly reduced or undetectable by Northern blot analysis of total RNA in the livers of rats treated with ciprofibrate [33].
• Changes in the profile of liver proteins in rats following induction of peroxisome proliferation by ciprofibrate, Wy-14,643 and DEHP have been analysed by high-resolution two-dimensional gel electrophoresis [34].

References