Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Clofibric Acid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMedDate not supplied

Species differences in the metabolic conjugation of clofibric acid and clofibrate in laboratory animals and man.

The urinary metabolites of single doses of clofibric acid (p-chlorophenoxyisobutyric acid), and its ethyl ester, clofibrate, have been investigated in rat, guinea pig, rabbit, dog, cat, ferret, and human volunteers. Human volunteers, rodents, and rabbits given clofibric acid excreted 60-90% of the 14C dose in the urine in 24 hr, and the only metabolite found was the ester glucuronide of clofibric acid, together with small amounts of the unchanged acid. In the dog, cat, and ferret, however, urinary excretion of 14C was much slower (23-39% of dose in 24 hr) and these species all formed the taurine conjugate of clofibric acid, excreted together with the unchanged acid. The ester glucuronide was found in the urine of dog and ferret but not cat. The fate of clofibrate, the ethyl ester of clofibric acid, in rat, guinea pig, rabbit, and man was similar to that of the parent acid. The characterization of the glucuronic acid and taurine conjugates of clofibric acid is described.

Animals↗
PubMed1990

The effect of beclobric acid and clofibric acid on peroxisomal beta-oxidation and peroxisome proliferation in primary cultures of rat, monkey and human hepatocytes.

The peroxisome-proliferating effects of clofibric acid and beclobric acid were studied in primary cultures of hepatocytes derived from rat, monkey (Macaca fascicularis) and human liver. Determination of peroxisomal fatty acid beta-oxidation and morphometrical analysis of the peroxisomal compartment were performed after incubation of 1-day-old hepatocyte cultures for 3 days with either compound. In rat liver cell cultures both compounds gave a 10-fold increase in peroxisomal beta-oxidation, a 3-fold increase in the relative number of peroxisomes and a 1.5-fold increase in the mean size of peroxisomes. Beclobric acid gave its maximal effect at a concentration of 10 microM, which is at least one order of magnitude lower than the maximum-effect concentration of clofibric acid. At concentrations greater than 300 microM beclobric acid was cytotoxic. No stimulation of peroxisomal fatty acid beta-oxidation was found in either monkey or human hepatocyte cultures. Morphometrical analysis also showed no increase in the peroxisomal compartment in cultures derived from these species, as indicated by the lack of increase in both relative number and size of peroxisomes. In all three species tested beclobric acid was equally cytotoxic for hepatocytes in vitro. These results are of relevance for the interpretation of the peroxisome-proliferating effects of clofibrate and similar compounds in rats. Since peroxisome proliferation may be correlated to increased hepatic tumour incidences in the rat, the absence of peroxisome proliferation in primates suggests the absence of tumourogenic activity by hypolipidemic compounds in these species.

Adult↗
PubMed1983

The analysis of [14C]clofibric acid glucuronide and [14C]clofibric acid in plasma and urine using high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the quantitation of [14C]clofibric acid glucuronide and [14C]clofibric acid using conventional scintillation counting. The assay has a linear relationship between the added and observed ratios of clofibric acid glucuronide: clofibric acid in the range of 0.001-0.6 for plasma and 0.5-100 for urine, and is able to quantitate previously unmeasurable concentrations of clofibric acid glucuronide in plasma.

Animals↗
PubMed1994

Modulation by dietary oils and clofibric acid of arachidonic acid content in phosphatidylcholine in liver and kidney of rat: effects on prostaglandin formation in kidney.

The manipulation of 20:4(n - 6) contents in phosphatidylcholine of liver and kidney of rats by dietary oils and p-chlorophenoxyisobutyric acid (clofibric acid) as well as the effects on the formation of prostaglandin E2 in kidney were studied. Three groups of rats were fed diets that contained either safflower oil (SO) or perilla oil (PO) or fish oil (FO) for 1 week. Each dietary group was divided into two groups. One group continued the same diet for another 1 week; the second group continued the same diet and received subcutaneous injections of clofibric acid once a day for 1 week. The content of 20:4(n - 6) in hepatic phosphatidylcholine was markedly lowered by feeding either FO or PO and was further decreased by the administration of clofibric acid. Feeding either FO or PO lowered the content of 20:4(n - 6) in hepatic phosphatidylethanolamine, whereas clofibric acid increased it. The decrease in the level of 20:4(n - 6) in serum phospholipid was produced by feeding either FO or PO and by the administration of clofibric acid as well. There was a high correlation for the levels of 20:4(n - 6) between hepatic phosphatidylcholine and serum phospholipid. The changes brought about by dietary oils and clofibric acid in renal phosphatidylcholine was similar to those observed in liver. The content of 20:4(n - 6) in renal phosphatidylcholine was highly correlated with the level of 20:4(n - 6) in serum phospholipid. Other phospholipids in kidney responded less sensitively to the manipulation by dietary oils and clofibric acid. These results suggest that the level of 20:4(n - 6) in renal phosphatidylcholine is regulated by the level of 20:4(n - 6) in hepatic phosphatidylcholine through the changes in serum level of 20:4(n - 6). Formation of prostaglandin E2 in kidney slices was dependent on the content of 20:4(n - 6) in renal phosphatidylcholine.

Animals↗
PubMed1996

Alterations by clofibric acid of metabolism of phosphatidylethanolamine in rat-liver.

Metabolic changes induced by p-chlorophenoxyisobutyric acid (clofibric acid) in hepatic phosphatidylethanolamine (PtdEtn) were studied. The treatment of rats with clofibric acid increased the hepatic concentrations of phosphatidylcholine (PtdCho), PtdEtn and phosphatidylinositol (PtdIns), but not phosphatidylserine (PtdSer). Among the phospholipids, the extent of increase of PtdEtn was the most prominent (1.91-fold on the basis of g liver and 2.73-fold on the basis of whole liver). Of the enzymes which are involved in the synthesis de novo of PtdEtn, the activity of cytidine 5'-triphosphate (CTP): phosphoethanolamine cytidylytransferase was reduced by the administration of clofibric acid to rats. The treatment of rats with this drug significantly decreased the serum concentration of free ethanolamine. Clofibric acid enhanced the activity of PtdSer decarboxylase and depressed the N-methylation in vivo of PtdEtn by inhibiting N-methyltransferase. Moreover, clofibric acid significantly depressed the turnover of PtdEtn, which was labeled in vivo with [3H]glycerol. These results suggest that, under the influence of clofibric acid, hepatocytes facilitate the pathway PtdCho-->PtdSer-->PtdEtn and reduce the turnover of PtdEtn, resulting in an expanded cellular pool of PtdEtn.

Animals↗
PubMed1985

Effects of long-term administration of clofibric acid on peroxisomal beta-oxidation, fatty acid-binding protein and cytosolic long-chain acyl-CoA hydrolases in rat liver.

Long-term effects of rho-chlorophenoxyisobutyric acid (clofibric acid) on inductions of peroxisomal beta-oxidation, fatty acid-binding protein and cytosolic acyl-CoA hydrolases in rat liver were studied. Male rats were fed clofibric acid at a dietary concentration of 0.25% for 22 weeks. The induction of peroxisomal beta-oxidation activity lasted throughout the long-term treatment of rats, the activity being a half that of rats treated with clofibric acid for 2 weeks. cytosolic long-chain acyl-CoA hydrolase I and II were both induced by the long-term and the short-term treatment of age-matched rats with clofibric acid, although the ability to induce hydrolase I decreased greatly by aging of rats. There was little difference in the inducing effect on fatty acid-binding protein between the long-term treatment and the short-term treatment. These results suggest that the inductions of peroxisomal beta-oxidation, fatty acid-binding protein and two cytosolic long-chain acyl-CoA hydrolases are essential responses of rats to clofibric acid (but not the brief events which occur in only the first stage of the continuous treatment with clofibric acid).

Animals↗
PubMed1994

The mechanism for the increased supply of phosphatidylcholine for the proliferation of biological membranes by clofibric acid, a peroxisome proliferator.

The metabolic changes induced by p-chlorophenoxyisobutyric acid (clofibric acid), a peroxisome proliferator, in hepatic glycerolipids for the supply of membrane phospholipids were studied. The administration of clofibric acid to rats caused hepatomegaly and an increase in hepatic contents of phosphatidylcholine (PtdCho) (1.13-fold on the basis of g liver and 1.50-fold on the basis of whole liver). The administration of the drug enhanced the formation in vivo of PtdCho from [3H]glycerol, which seemed to be due to the increase in activity of CTP:phosphocholine cytidylyltransferase. On the other hand, clofibric acid depressed the activity of phosphatidylethanolamine N-methyltransferase. The in vivo study using [3H]glycerol revealed that clofibric acid slightly reduced the secretion of PtdCho into circulation. On the other hand, the drug did not affect the turnover of PtdCho. These results may elucidate the metabolic alterations by which clofibric acid increases hepatic mass of PtdCho. The facilitated biosynthesis of PtdCho by the drug seemed to lead to the increased formation of phosphatidylserine and subsequently phosphatidylethanolamine. Physiological significance of the alterations in glycerolipid metabolism by clofibric acid was discussed in relation to biological action of the drug.

Animals↗
PubMed2001

Metabolic alterations by clofibric acid in the formation of molecular species of phosphatidylcholine in rat liver.

The mechanism by which p-chlorophenoxyisobutyric acid (clofibric acid) induces striking changes in the proportion of the molecular species of phosphatidylcholine (PC) in rat liver was studied. Treatment of rats with clofibric acid strikingly increased the content of 1-palmitoyl-2-oleoyl (16:0-18:1) PC, but decreased the contents of 1-palmitoyl-2-docosahexaenoyl (16:0-22:6), 1-stearoyl-2-arachidonoyl (18:0-20:4), and 1-stearoyl-2-linoleoyl (18:0-18:2) PC; the drug did not change the content of 1-palmitoyl-2-arachidonoyl (16:0-20:4) PC. The mechanism underlying these changes has been investigated with regard to the in vivo formation of the molecular species of PC by: (i) de novo synthesis, (ii) reacylation, and (iii) methylation of phosphatidylethanolamine (PE). We found that (i) the incorporation of [3H]glycerol, which was injected intravenously, into 16:0-18:1 diacylglycerol (DG) and 16:0-18:1 PC was increased markedly by clofibric acid feeding without changing the substrate specificity of CDP-choline:DG cholinephosphotransferase, (ii) the in vivo formation of 16:0-18:1 and 16:0-20:4 PC from 1-16:0-[3H]glycerophosphocholine (GPC), which was injected intraportally, was increased markedly by clofibric acid feeding, and (iii) the incorporation of [14C]ethanolamine, which was injected intravenously into 16:0-22:6, 18:0-22:6, and 18:0-20:4 PC, was decreased by clofibric acid feeding; the extent of the decrease in 16:0-20:4 PC was less than that of 18:0-20:4 PC. It was concluded, therefore, that (i) clofibric acid selectively increased the content and proportion of 16:0-18:1 PC by enhancing both the CDP-choline pathway and the remodeling of the pre-existing PC molecule, and (ii) the drug kept the content of 16:0-20:4 PC unchanged by stimulating the remodeling of the pre-existing PC molecule, whereas the formation of other more long chain, polyunsaturated molecular species, such as 16:0-22:6, 18:0-22:6, and 18:0-20:4, was decreased owing to the suppression of PE methylation.

Acylation↗
PubMed1993

Alterations by clofibric acid of glycerolipid metabolism in rat-kidney.

Alterations induced by p-chlorophenoxyisobutyric acid (clofibric acid) in glycerolipid metabolism in rat-kidney were studied. (1) The treatment of rats with clofibric acid markedly decreased renal level of triacylglycerol, which seemed to be due to a reduced formation of triacylglycerol, since the in vivo incorporation of [14C]oleic acid (18:1), [14C]linoleic acid (18:2) and [3H]glycerol into triacylglycerol was decreased in clofibric acid-fed rats. (2) The administration of clofibric acid to rats increased proportions of 18:1 and 18:2 and decreased a proportion of arachidonic acid (20:4) in phosphatidylcholine; the contents of two major molecular species of renal diacylglycerophosphocholine (diacyl-GPC), palmitoyl-arachidonoyl (16:0-20:4) and stearoylarachidonoyl (18:0-20:4), were both decreased markedly. The treatment did not alter renal content of phosphatidylcholine. (3) By contrast, clofibric acid changed, to a lesser extent, the composition of molecular species of diacylphosphatidylethanolamine. (4) The decrease in the level of diacyl-GPC that contains 20:4 seemed to be due to the clofibric acid-caused reduction in the concentration of free 20:4 in kidney. The reduction in renal concentration of free 20:4 seemed to be caused by a decrease in serum concentration of lipids that contain 20:4, but not by a decrease in the activities of desaturation and chain elongation that participate in biosynthesis of 20:4. (5) The reduction by clofibric acid in the renal content of diacyl-GPC containing 20:4 resulted in the decrease in the formation of prostaglandin E2 in kidney.

Animals↗
PubMed1987

Effects of long-term administration of clofibric acid on stearoyl-CoA desaturase, 1-acylglycerophosphorylcholine acyltransferase and fatty acyl composition of microsomal phosphatidylcholine in rat liver.

Long-term effects of p-chlorophenoxyisobutyric acid (clofibric acid) on inductions of stearoyl-CoA desaturase and 1-acylglycerophosphorylcholine (1-acyl-GPC) acyltransferase, and on changes in fatty acyl composition of microsomal lipid in rat liver were studied. Male rats were fed clofibric acid at a dietary concentration of 0.25% for 2 or 22 weeks. Inductions of stearoyl-CoA desaturase and 1-acyl-GPC acyltransferase lasted throughout the long-term treatment and were the same as those of either young or aged rats which were treated with clofibric acid for 2 weeks. The long-term treatment of rats with clofibric acid scarcely affected components of stearoyl-CoA desaturation system other than terminal desaturase. In accordance with the induction of stearoyl-CoA desaturase, the increase in the proportion of octadecenoic acid in hepatic lipid lasted throughout the 22-week treatment. In the case of both of the long-term treatment and the short-term treatment of rats, the increase in the proportion of octadecenoic acid in microsomal phosphatidylcholine was due to the marked increase in the proportion of octadecenoic acid in position 2, but not position 1, of phosphatidylcholine. These changes in fatty acyl composition of phosphatidylcholine were not due to the alteration of the content of phosphatidylcholine in liver.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1984

Modification by clofibric acid of acyl composition of glycerolipids in rat liver. Possible involvement of fatty acid chain elongation and desaturation.

Administration of p-chlorophenoxyisobutyric acid (clofibric acid) to rats induced a marked change in acyl composition of hepatic glycerolipids; a considerable increase in the proportion of octadecenoic acid (18:1) was accompanied by a marked decrease in the proportion of octadecadienoic acid (18:2). Among the glycerolipids, the changes in the proportions of 18:1 and 18:2 were the most marked in phosphatidylcholine. The change in the acyl composition of phosphatidylcholine paralleled the change in free fatty acid composition in microsomes. The treatment of rats with clofibric acid resulted in a 2.3-fold increase in activity of microsomal palmitoyl-CoA chain elongation and a 4.8-fold increase in activity of stearoyl-CoA desaturation. The activities of acyl-CoA synthetase, 1-acylglycerophosphate acyltransferase and 1-acylglycerophosphorylcholine acyltransferase in hepatic microsomes were increased approx. 3-, 1.7- and 3.6-times, respectively, by the treatment of rats with clofibric acid. These findings are discussed with respect to the role of fatty acid modification systems in the regulation of acyl composition of phosphatidylcholine.

Acyl Coenzyme A↗
PubMed1992

Reduction by clofibric acid of serum arachidonic acid in rats. Effect on the acyl composition of renal phospholipids.

Alterations induced by p-chlorophenoxyisobutyric acid (clofibric acid) in the composition of phosphatidylcholine and cholesterol esters in serum and their influence on the composition of phosphatidylcholine in the kidney were studied. Rats of different ages responded differently to the drug in terms of the levels of arachidonic acid (20:4) and linoleic acid (18:2) in the phosphatidylcholine and cholesterol esters in the serum. Administration of clofibric acid to 26-week-old rats for 2 weeks caused a marked decreased in the relative level of 20:4 in phosphatidylcholine and cholesterol esters in serum, whereas similar treatment of 6-week-old rats resulted in a reduction of 18:2 and, to a lesser extent, of 20:4 in serum lipids. The decrease in phosphatidylcholine that contained 20:4 in the serum of old rats was mainly due to a decrease in the concentration of stearoyl-arachidonoyl (18:0-20:4) species. The decrease in cholesterol arachidonate in serum caused by the treatment of old rats with clofibric acid seemed to be due to a reduction in the relative level of serum phosphatidylcholine containing 20:4. The marked reduction in serum lipids that contained 20:4 caused a decrease in the relative level of 20:4 in renal phospholipids, in particular, a decrease in the proportion of palmitoyl-arachidonoyl (16:0-20:4) and 18:0-20:4 phosphatidylcholine.

Age Factors↗
PubMed1999

Effects of tiadenol and di-(2-ethylhexyl)phthalate on the metabolism of phosphatidylcholine and phosphatidylethanolamine in the liver of rats: comparison with clofibric acid.

Metabolic changes induced by 2,2'-(decamethylenedithio)diethanol (tiadenol) and di-(2-ethylhexyl)phthalate (DEHP) in the biosynthesis of phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) in rat liver were compared with changes induced by p-chlorophenoxyisobutyric acid (clofibric acid). Treatment of rats with either tiadenol or DEHP increased the hepatic contents of PtdCho and PtdEtn, as was observed with clofibric acid treatment. The administration of tiadenol, DEHP, or clofibric acid slightly, but significantly, increased, in common, the activity of CTP:phosphocholine cytidylyltransferase, a key enzyme for the synthesis de novo of PtdCho, and suppressed the activity of PtdEtn N-methyltransferase. With regard to the enzymes involved in the synthesis of PtdEtn, the three peroxisome proliferators enhanced the activity of phosphatidylserine (PtdSer) decarboxylase and markedly decreased the activity of CTP:phosphoethanolamine cytidylyltransferase. Treatment of rats with the three compounds markedly increased, in common, the content and the proportion of the molecular species of PtdCho containing oleic acid (18:1), but considerably decreased the proportion of the molecular species of PtdCho containing linoleic acid (18:2) in the liver, resulting in a striking decrease in the concentration of the molecular species of PtdCho containing 18:2 in the serum. The present study suggests that the administration of peroxisome proliferators to rats increases the contents of hepatic PtdCho and PtdEtn for hepatomegaly and proliferation of organelles by the same mechanism, irrespective of their chemical structures.

Animals↗
PubMed1982

Increased activity of stearoyl-CoA desaturation in liver from rat fed clofibric acid.

Male rats were fed a diet containing 0.5% (w/w) p-chlorophenoxyisobutyric acid (clofibric acid), a hypolipidemic drug. Activities of stearoyl-CoA desaturation in hepatic microsomes were increased approx. 4 times following the administration of clofibric acid for 7 days. An increase in the activity of desaturation of stearic acid was also observed in the liver of clofibric acid-fed rats in vivo. The increase in the activity of microsomal stearoyl-CoA desaturation by clofibric acid-feeding was due to the increase in the activity of terminal desaturase as measured by the rate constant for cytochrome b5 reoxidation, but not due to the changes in cytochrome b5 content and NADH-cytochrome b5 reductase activity. Increases in the activity of stearoyl-CoA desaturation by clofibric acid-feeding were also observed in rats of hormonally altered state, such as diabetic rats, hyperthyroid rats and hypothyroid rats. Percentages of octadecenoic acid in total fatty acid of hepatic lipid were increased with the increase in the activity of stearoyl-CoA desaturation.

Acyl Coenzyme A↗
PubMed1987

Effects of clofibric acid and tiadenol on cytosolic long-chain acyl-CoA hydrolase and peroxisomal beta-oxidation in liver and extrahepatic tissues of rats.

The effects of two peroxisome proliferators, p-chlorophenoxyisobutyric acid (clofibric acid) and 2,2'-(decamethylenedithio)diethanol (tiadenol), on cytosolic long-chain acyl-CoA hydrolase and peroxisomal beta-oxidation were studied in several organs of rat. Among organs of control rats, the brain had the highest activity of long-chain acyl-CoA hydrolase, followed by testis, and a low activity was found in other tissues. Administration of the peroxisome proliferators caused a marked increase in activity of long-chain acyl-CoA hydrolase in both liver and intestinal mucosa and a slight increase in the activity in kidney, but little affected acyl-CoA hydrolase activity in either brain, testis, heart, spleen and skeletal muscle. In accordance with the change in the activity of acyl-CoA hydrolase, the activity of peroxisomal beta-oxidation was markedly increased in liver, intestinal mucosa and kidney, and a slight increase was found in brain and testis, whereas peroxisome proliferators little affected the activity in other organs tested. Gel filtration of cytosol from intestinal mucosa showed that clofibric acid caused an appearance of a new peak in intestinal mucosa. Although cytosol of liver, intestinal mucosa, brain and testis contained two 4-nitrophenyl acetate esterases with different molecular weights (about 105,000 and about 55,000), these esterases are different from cytosolic long-chain acyl-CoA hydrolases of these four organs in respect of molecular weight. The administration of clofibric acid little affected cytosolic 4-nitrophenyl acetate esterases. Comparative studies on cytosolic long-chain acyl-CoA hydrolases from these four organs showed that liver hydrolase I (molecular weight of about 80,000) had properties similar to those of brain and testis enzymes. On the other hand, intestinal mucosa enzyme was different from either hepatic hydrolase I or II (molecular weight of about 40,000). The results from the present study suggest that inductions of peroxisomal beta-oxidation and cytosolic long-chain acyl-CoA hydrolases are essential responses of rats to peroxisome proliferators not only in liver but also in intestinal mucosa and that induced hydrolases are not attributable to non-specific esterases.

Animals↗
PubMed1986

Inducing effects of clofibric acid on 1-acylglycerophosphorylcholine acyltransferase in kidney and intestinal mucosa of rats.

Administration of p-chlorophenoxyisobutyric acid (clofibric acid) markedly increased the activity of microsomal 1-acylglycerophosphorylcholine (1-acyl-GPC) acyltransferase in kidney, intestinal mucosa and liver, but not in brain, heart, lung, spleen, testis or skeletal muscle. In both kidney and liver, a marked dose-dependent increase in the activities of both microsomal 1-acyl-GPC acyltransferase and peroxisomal beta-oxidation was observed. In the rats treated with clofibric acid at a relatively low dose, the increase in the activity of 1-acyl-GPC acyltransferase in kidney was more marked than that in liver. The extent of the relative increase in the activity of 1-acyl-GPC acyltransferase to the activity of peroxisomal beta-oxidation in kidney was more marked than that in liver. The increased activity of 1-acyl-GPC acyltransferase in both kidney and liver lasted throughout the 8-week treatment period of rat with clofibric acid.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1987

Stereospecificity of the chloride ion channel: the action of chiral clofibric acid analogues.

2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride membrane conductance (GCl) in rat striated muscle. In the present study chiral analogues of CPIB (2-(p-chlorophenoxy)propionic acid (2) and 2-(p-chlorophenoxy)butyric acid (3)) have been tested to evaluate the influence of chirality on Cl ion flux in the channel. The results showed that the chloride channel conductance strongly depends on the absolute configuration: in fact, the S-(-) isomers of the tested compounds strongly decreased the GCl of skeletal muscle membrane, whereas the R-(+) isomers were virtually ineffective. These data allow the hypothesis that, like other ion channels present in various biological systems, the chloride channel of skeletal muscle membrane could also have a stereospecific binding site (or receptor) regulating chloride ion flux.

2-Methyl-4-chlorophenoxyacetic Acid↗