Disease relevance of clofibric acid

• Body weight, kidney weight, and systemic blood pressure were not significantly altered by clofibric acid [1].
• Rats subjected to right nephrectomy and two-thirds segmental infarction of the left kidney (5/6 nephrectomy) were treated for 10 weeks with the lipid-lowering agent clofibric acid [1].
• The incidence rate per 1000 for myocardial infarction was 30.3 for control subjects, 53.6 for the IHE group, and 55.6 for the IHE plus clofibric acid group [2].
• Two stereoisomeric analogs of clofibric acid, (-)- and (+)-desmethyl clofibric acid, also caused a significant inhibition of HSV-1 replication [3].
• Clofibric acid down-regulation of metallothionein IIA in HepG2 human hepatoma cells [4].

High impact information on clofibric acid

• Amphipathic carboxylates such as clofibric acid have been used in man as hypolipidaemic agents and in rodents they stimulate the proliferation of peroxisomes [5].
• Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor [6].
• Conversely, when a rat liver cytosol containing multiple members of the HSP70 family was passed through an ATP-agarose column, and eluted with clofibric acid, only P72 (HSC70) was eluted [7].
• These results suggest that clofibric acid, a peroxisome proliferator, preferentially interacts with P72 at or near the ATP binding site [7].
• We now show that this protein is homologous with the heat shock protein HSP70 family by analysis of amino acid sequences of isolated peptides from trypsin-treated clofibric acid binding protein and by cross-reactivity with a monoclonal antibody raised against the conserved region of the 70-kDa heat shock proteins [7].

Chemical compound and disease context of clofibric acid

• We examined the effects of various peroxisome proliferators (PPs) such as the hypolipidaemic agents clofibric acid (CLO), bezafibrate (BEZA), ciprofibrate (CIPRO) and nafenopin (NAFE) and the plasticizer di-(2-ethylhexyl)phthalate (DEHP) on peroxisomal enzyme activities, apoptosis and DNA synthesis in rat FaO and human HepG2 hepatoma cell lines [8].
• Whether acyl glucuronides also attack nuclear DNA is unknown, although the acyl glucuronide formed from clofibric acid was recently found to decrease the transfection efficiency of phage DNA and generate strand breaks in plasmid DNA in vitro [9].
• Clofibric acid (CL) is a compound used to control hypertriglyceridemia, and ethacrynic acid (ET) is administered to enhance diuresis [10].
• To contribute to the understanding of the hypolipidemic action of etofibrate, which is the 1,2-ethandiol ester of clofibric acid and nicotinic acid, 300 mg of this drug/kg body weight or of the medium were administered daily by a stomach tube to normolipidemic rats [11].
• Induction of hydrolase I, hydrolase II, peroxisomal beta-oxidation and hepatomegaly caused by clofibric acid (rho-chlorophenoxyisobutyric acid) administration was investigated in relation to alterations in hormonal state of glucocorticoid, thyroid hormone and insulin [12].

Biological context of clofibric acid

• However, clofibric acid did not significantly alter single nephron glomerular filtration rates (95 +/- 2.1 nl/min in treated versus 97.0 +/- 6.2 nl/min in untreated, p greater than 0.05) or glomerular capillary pressures (56.6 +/- 1.5 mm Hg in treated versus 57.8 +/- 0.8 mm Hg in untreated, p greater than 0.05) in 5/6 nephrectomy rats [1].
• Liver gene expression profiles of rats treated with clofibric acid: comparison of whole liver and laser capture microdissected liver [13].
• Gene transfer experiments indicate that induction by the peroxisome proliferators, clofibric acid and WY-14,643, of luciferase expression driven by the promoter and 5'-flanking sequences of the rabbit cytochrome P450 4A6 gene (CYP4A6) is dependent on cotransfection of expression plasmids for the peroxisome proliferator-activated receptor, PPAR [14].
• Saliva and plasma levels and plasma protein binding of clofibrinic acid in uremic patients [15].
• Elevated levels of 8-OHdG were not detected in DNA isolated from nuclear fractions of livers from rats fed clofibric acid for 22 weeks, indicating the dependence of PP-induced oxidative DNA damage on extranuclear components of samples for DNA isolation [16].

Anatomical context of clofibric acid

• Ciprofibrate was also more potent than clofibric acid as an inducer of the 60 and 80 kD proteins in hepatocytes [17].
• The results show that bezafibrate, gemfibrozil and clofibric acid, do induce differentiation in human myeloid leukaemia cell lines as indicated by several differentiation markers [18].
• We have determined the comparative activities of peroxisomal proliferators, ciprofibrate and clofibric acid on various hepatic parameters associated with endoplasmic reticulum, mitochondria and peroxisomes in primary cultures of rat hepatocytes [17].
• 2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride membrane conductance (GCl) in rat striated muscle [19].
• The rate of cornified envelope formation was increased 3-fold in keratinocytes maintained in low calcium (0.03 mM) and incubated in the presence of clofibric acid, a potent PPARalpha activator [20].

Associations of clofibric acid with other chemical compounds

• Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver [21].
• In cultured hepatocytes, ciprofibrate was about 30-fold more active than clofibric acid for the stimulation of carnitine acetyltransferase, laurate hydroxylase and fatty acylCoA oxidase activities [17].
• The inductions of delta 6 and delta 5 desaturations were brought about by the treatment of rats with 2,2'-(decamethylenedithio)diethanol or di-(2-ethylhexyl)-phthalate, peroxisome proliferators structurally unrelated to clofibric acid, as well [22].
• The inhibitory effects of 4-(4-chlorophenyl)-2-hydroxytetronic acid (2a) on human platelet aggregation and [14C]serotonin secretion were compared with clofibric acid (1b), the hydrolysis product of clofibrate (1a) [23].
• Male Sprague-Dawley rats were given daily oral doses of either corn oil (control), 80 mg/kg nafenopin (NAF), 50 mg/kg methylclofenapate (MCP), 50 mg/kg Wy-14,643 (WY) or 250 mg/kg clofibric acid (CA) for 7 days [24].

Gene context of clofibric acid

• Insulin (200 mg/L) up-regulated VLDLR message in JEG-3 cells 2-fold, as did the fibrate hypolipidemic drug, clofibric acid [25].
• In NIH 3T3 transfected cells, PPAR gamma1 was activated by peroxisome proliferators such as Wy-14643, clofibric acid and Ly-171883 causing induction of the target marker gene [26].
• The known PPAR recognition elements (PPRE), which were reported to be involved in the induction of CYP4A6 by clofibric acid, were not observed within the 5'-flanking region of the CYP4A11 gene [27].
• Co-treatment of rats with S.III and clofibric acid (CA) caused a 40-50% decrease in the induced levels of CYP1A1 and CYP1A2 protein, mRNA expression and their metabolic activities and reduced AhR protein expression [28].
• CYP1A1/2, CYP2B1, CYP3A2, CYP4A1, and CYP2E1 were induced by the addition of 3-methylcholanthrene, phenobarbital, pregnenolone-16alpha-carbonitrile, clofibric acid, and ethanol, respectively [29].

Analytical, diagnostic and therapeutic context of clofibric acid

• Using affinity chromatography, we had previously isolated a protein that binds to clofibric acid [7].
• Inulin clearance was greater in clofibric acid-treated than in untreated 5/6 nephrectomy rats (0.28 +/- 0.02 versus 0.22 +/- 0.02 ml/min 100 g body wt, p less than 0.05) [1].
• The free fraction of clofibrinic acid in plasma is higher (p less than 0.02) in long-term hemodialysis patients (0.0915 +/- 0.0141) than in nondialysis patients (0.0715 +/- 0.0143) [15].
• RESEARCH DESIGN AND METHODS: Within the intervention group, the benefit of clofibric acid was evaluated in a double-blind study [2].
• However, quantitation of a PCR amplified region from the D-loop of mtDNA demonstrated a 2- to 3-fold increase in the relative amount of mtDNA in DNA isolated from unfractionated liver homogenates following 3, 11, and 22 weeks exposure to Wy or CA (22 weeks only) [30].

References