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PubMed1985

Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate)), a peroxisome proliferator.

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.

Administration, Oral↗
PubMed1976

Effect of clofibrate treatment on carnitine acyltransferases in different subcellular fractions of rat liver.

The subcellular distribution of carnitine acetyl-, octanoyl-, and palmitoyl- transferase in the livers of normal and clofibrate-treated male rats was studied with isopycnic sucrose density gradient fractionation. In normal liver 48% of total carnitine acetyltransferase activity was peroxisomal, 36% of the activity located in mitochondria and 16% in a membranous fraction containing microsomes. Carnitine octanoyltransferase and carnitine palmitoyltransferase were confined almost totally (77--81%) to mitochondria in normal liver. Clofibrate treatment increased the total activity of carnitine acetyltransferase over 30 times, whereas the total activities of the other two transferases were increased only 5-fold. From the three different subcellular carnitine acetyltransferases the mitochondrial one was most responsive to clofibrate treatment, i.e. the rise in mitochondrial activity was over 70-fold as contrasted to the 6- and 14-fold rises in peroxisomal and microsomal activities, respectively. After treatment mitochondria contained 79% of total activity. It is concluded that the clofibrate-induced increase of carnitine acetyltransferase activity is not due to the peroxisomal proliferation that occurs during clofibrate treatment. The rise in peroxisomal activity contributed only 8% to the total increase. After clofibrate treatment the greatest part of carnitine octanoyl- and palmitoyltransferase activities were located in mitochondria but a considerable amount of both activities was found also in the soluble fraction of liver.

Acyltransferases↗
PubMed1996

Change of the sex-dependent response to clofibrate in F344 rat liver during postnatal development.

Although it has been reported that male rats are more responsive than females to peroxisome proliferation induced by clofibrate, these sex differences have been confirmed in young adult rats. Using 4-, 8-, and 12-week-old F344 rats, postnatal change of the sex-dependent response to clofibrate was investigated. These animals were administered 200 mg/kg body wt./day clofibrate by gavage for 7 days. In 4-week-old rats clofibrate-dependent changes (hepatomegaly, induction of hepatic microsomal and peroxisomal enzymes, proliferation of smooth endoplasmic reticulum and peroxisomes of hepatocytes) were slight in both sexes. In 8- and 12-week-old rats clofibrate-induced changes of males were moderate, whereas those of females were slight. These results suggest that the responsiveness of immature rat to clofibrate is weak and in males the susceptibility is gradually strong during postnatal development.

Administration, Oral↗
PubMed2004

PPARalpha agonists clofibrate and gemfibrozil inhibit cell growth, down-regulate hCG and up-regulate progesterone secretions in immortalized human trophoblast cells.

We studied effects of PPARalpha agonists clofibric acid and gemfibrozil on cell growth and functions of immortalized human extravillous trophoblast cells. Levels of DNA and protein gradually increased during incubation for 4 days. Gemfibrozil (>0.25mM) and clofibric acid (2.5mM) suppressed the rate of increase in DNA and protein. Specific activities of fatty acyl-CoA oxidase and catalase were increased to about 1.2-2.0 times the control value by 0.05mM gemfibrozil and 1.0 and 2.5mM clofibric acid after incubation for 3 days. Acid phosphatase activity showed a small increase in response to both agents, but esterase activity changed little. The secretion of progesterone from the cells into the medium was increased by 0.25mM gemfibrozil and 1.0 and 2.5mM clofibric acid after incubation for 3 days, but that of human chorionic gonadotropin (hCG) was decreased by 0.35mM gemfibrozil and 2.5mM clofibric acid. The specific activity of lactate dehydrogenase in the cells was hardly changed at all after incubation for 3 days. These results suggest that gemfibrozil and clofibric acid inhibit the proliferation of trophoblast cells. Cell metabolism is probably affected by both agents. The two agents may down-regulate hCG and up-regulate progesterone secretions.

Anticholesteremic Agents↗
PubMed2005

Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23.

The pregnane X receptor (PXR) interacts with a vast array of structurally dissimilar chemicals and confers induction of several major types of drug metabolizing enzymes such as cytochrome P450s (CYP). We previously reported that the expression of PXR was markedly increased in rats treated with clofibrate and perfluorodecanoic acid (PFDA). The present study was undertaken to test the hypothesis that induced expression of PXR increases PXR ligand-dependent induction on CYP3A23. Rat hepatocytes were treated with clofibrate or PFDA individually, or along with PXR ligand pregnenolone 16alpha-carbonitrile (PCN), and the levels of PXR and CYP3A23 were determined by Western blots. Both clofibrate and PFDA markedly increased the expression of PXR with PFDA being more potent, and the induction was abolished by actinomycin D, an inhibitor for mRNA synthesis. As expected, PCN alone markedly induced the expression of CYP3A23. Interestingly, co-treatment with clofibrate enhanced the induction, whereas co-treatment with PFDA suppressed it. Clofibrate and PFDA represent multi-classes of chemicals called peroxisome proliferators including many therapeutic agents and industrial pollutants. The opposing effects of clofibrate and PFDA on the PCN-induced expression of CYP3A23 suggest that peroxisome proliferators likely increase the expression of PXR but differentially alter its ligand-dependent induction. The interaction between PXR inducer and ligand provides a novel mechanism on how functionally and structurally distinct chemicals cooperatively regulate the expression of xenobiotic-metabolizing enzymes and transporters.

Animals↗
PubMed2006

Peroxisome proliferator-activated receptor alpha agonist, clofibrate, has profound influence on myocardial fatty acid composition.

The hypolipidemic fibrates have been identified as agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha), which plays a critical role in the regulation of cardiac fatty acid metabolism. Despite the widespread clinical use of fibrates, their role in myocardial oxidative stress and fatty acid composition is less known. In this study, male Sprague-Dawley rats were treated with either vehicle (olive oil, 1 ml/kg) or clofibrate (300 mg/kgday i.p.) for 1-14 days. Lipid peroxidation in heart homogenate was determined by thiobarbituric acid reactive substance (TBARS) assay. Results show that hearts from clofibrate-treated rats are more susceptible to FeSO(4)-induced TBARS production. The antioxidants including catalase and glutathione-related enzymes were marginally affected. We demonstrated that myocardial fatty acid composition was dramatically altered by clofibrate treatment. In hearts from clofibrate-treated rats, the principal n-6 polyunsaturated fatty acids (PUFAs), linoleic acid (C18:2 n-6) and arachidonic acid (C20:4 n-6), was significantly reduced, while the content of the principal n-3 PUFA, docosahexaenoic acid (C22:6 n-3), was markedly increased. The overall effect was to reduce n-6/n-3 ratio and increase the unsaturation extent of myocardial fatty acids. Functional study showed that hearts from clofibrate-treated rats had an improved recovery of post-ischemic contractile function and reduced ischemia/reperfusion (I/R)-induced infarct size. The data shows that clofibrate has a profound impact on cardiac fatty acid composition, which may contribute to its cardioprotective effect.

Animals↗
PubMed2004

Dietary clofibrate inhibits induction of hepatic antioxidant enzymes by chronic estradiol in female ACI rats.

Excess production of H2O2 has been implicated in oncogenesis. The object of the present study was twofold: first, to determine the influence of chronic estradiol (E2) on the activities of selected hepatic antioxidant enzymes in female ACI rats, a strain that is highly sensitive to the induction of estrogen dependent mammary tumors; secondly, to evaluate the actions of dietary clofibrate, a peroxisome proliferator, on activities of these enzymes in control and E2-treated ACI rats. Enzymes selected for study were: NAD(P)H quinone oxidoreductase (NQO1), glutathione S-transferase (GST) and glutathione peroxidase (GPx). Cytosolic catalase (CAT) was also measured as an index of peroxisome proferation in control and E2- treated animals. E2 was administered chronically over 6 and 12 week periods from cholesterol pellet implants containing either 1 or 3 mg E2. Animals were fed AIN-76A diets with or without 0.4% clofibrate over the experimental period. NQO1 and GST but not GPx were induced to varying degrees (NQO1 about 300%, and GST about 45-97%) by chronic E2-treatment. E2-induced increases in these activities were completely prevented in rats exposed to dietary clofibrate. Dietary clofibrate also caused slight but significant reductions in baseline activities of NQO1, GST and GPx in control animals. Serum E2 levels, increased approximately 540% in a dose-dependent manner, and were not altered by dietary clofibrate. It is concluded that chronic E2 treatment markedly induces several important hepatic antioxidant enzymes in female ACI rats, and induction of these activities by E2 is inhibited completely by dietary clofibrate. Both of these actions have the potential to markedly influence the profile of E2 metabolites exported from the liver to E2 sensitive extrahepatic tissues and influence the initiation and progression of hormone-dependent tumors.

Animals↗
PubMed2000

Changes in isoprenoid lipid synthesis by gemfibrozil and clofibric acid in rat hepatocytes.

We studied whether gemfibrozil and clofibric acid alter isoprenoid lipid synthesis in rat hepatocytes. After incubation of the cells with the agent for 74 hr, [(14)C]acetate or [(3)H]mevalonate was added, and the cells were further incubated for 4 hr. Gemfibrozil and clofibric acid increased ubiquinone synthesis from [(14)C]acetate and [(3)H]mevalonate. The effect of gemfibrozil was greater than that of clofibric acid. Also, gemfibrozil decreased dolichol synthesis from [(14)C]acetate and [(3)H]mevalonate. However, clofibric acid increased dolichol synthesis from [(3)H]mevalonate. Gemfibrozil decreased cholesterol synthesis from [(14)C]acetate and [(3)H]mevalonate. Clofibric acid decreased cholesterol synthesis from [(14)C]acetate, but did not affect synthesis from [(3)H]mevalonate. These results suggest that both agents, at different rates, activate the synthetic pathway of ubiquinone, at least from mevalonate. Gemfibrozil may inhibit the synthetic pathway of dolichol, at least from mevalonate. Contrary to gemfibrozil, clofibric acid may activate the synthetic pathway of dolichol from mevalonate. Gemfibrozil may inhibit the synthetic pathway of cholesterol from mevalonate in addition to the pathway from acetate to mevalonate inhibited by both agents.

Acetates↗
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↗
PubMed1998

Effect of clofibrate on the chiral inversion of ibuprofen in healthy volunteers.

OBJECTIVES: To determine the influence of the hypolipidemic drug clofibrate on the stereoselective metabolism of ibuprofen in humans. METHODS: Healthy male subjects (n = 12) ingested a dose of 400 mg pseudoracemic ibuprofen (200 mg R-ibuprofen, 160 mg S-ibuprofen, and 40 mg 13C-S-ibuprofen) on two occasions after either pretreatment with clofibrate (2 gm/day over 1 week) or no pretreatment in a randomized order. RESULTS: When subjects were pretreated with clofibrate, clearances of R-ibuprofen and 13C-S-ibuprofen increased significantly from 55.0 and 66.4 ml/min to 186.2 and 106.7 ml/min (p < 0.01), respectively. This increase was similarly reflected in the clearance by inversion of R-ibuprofen (control, 36.0 ml/min; treated, 118.8 ml/min; p < 0.01), as well as in the clearance by noninversion (control, 19.0 ml/min; treated, 67.4 ml/min; p < 0.01). Unbound clearance values significantly increased for R-ibuprofen (control, 19.5 L/min; treated, 38.7 L/min) but not for 13C-S-ibuprofen (11.8 versus 10.6 L/min, respectively). The fractional inversion of ibuprofen calculated from the urinary metabolite data was increased after clofibrate pretreatment (clofibrate group, 66.4%; control, 53.5%; p < 0.01). However, this was not evident when fractional inversion was calculated from the plasma concentration-time data for the unmetabolized drug. CONCLUSIONS: Clofibrate altered the stereoselective disposition of ibuprofen in healthy volunteers by increased formation of R-ibuprofenoyl-coenzyme A rather than by an effect on oxidative metabolism of ibuprofen. This interaction has potential therapeutic implications.

Adult↗
PubMed2001

Mechanism of clofibrate hepatotoxicity: mitochondrial damage and oxidative stress in hepatocytes.

Peroxisome proliferators have been found to induce hepatocarcinogenesis in rodents, and may cause mitochondrial damage. Consistent with this, clofibrate increased hepatic mitochondrial oxidative DNA and protein damage in mice. The present investigation aimed to study the mechanism by which this might occur by examining the effect of clofibrate on freshly isolated mouse liver mitochondria and a cultured hepatocyte cell line, AML-12. Mitochondrial membrane potential (Delta Psi(m)) was determined by using the fluorescent dye 5,5',6,6'-tetrachloro-1,1', 3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1) and tetramethylrhodamine methyl ester (TMRM). Application of clofibrate at concentrations greater than 0.3 mM rapidly collapsed the Delta Psi(m) both in liver cells and in isolated mitochondria. The loss of Delta Psi(m) occurred prior to cell death and appeared to involve the mitochondrial permeability transition (MPT), as revealed by calcein fluorescence studies and the protective effect of cyclosporin A (CsA) on the decrease in Delta Psi(m). Levels of reactive oxygen species (ROS) were measured with the fluorescent probes 5-(and-6)-carboxy-2',7'-dichlorofluorescein diacetate (DCFDA) and dihydrorhodamine 123 (DHR123). Treatment of the hepatocytes with clofibrate caused a significant increase in intracellular and mitochondrial ROS. Antioxidants such as vitamin C, deferoxamine, and catalase were able to protect the cells against the clofibrate-induced loss of viability, as was CsA, but to a lesser extent. These results suggest that one action of clofibrate might be to impair mitochondrial function, so stimulating formation of ROS, which eventually contribute to cell death.

Animals↗
PubMed1999

Clofibrate inhibits membrane trafficking to the Golgi complex and induces its retrograde movement to the endoplasmic reticulum.

Insights into the function of the Golgi complex have been provided by experiments performed with various inhibitors of membrane trafficking, such as the macrocyclic lactone brefeldin A (BFA), a compound that inhibits constitutive secretion, prevents the formation of coatomer-coated transport vesicles, and stimulates the retrograde movement of Golgi resident enzymes back to the ER. We show here that the structurally unrelated compound clofibrate, a peroxisome proliferator (PP) and hypolipidemic agent, also reversibly disrupts the morphological and functional integrity of the Golgi complex in a manner similar to BFA. In the presence of clofibrate, the forward transport of newly synthesized secretory proteins from the ER to the Golgi is dramatically inhibited. Moreover, clofibrate causes Golgi membranes to travel rapidly in a microtubule-dependent manner back to the ER, forming a hybrid ER-Golgi tubulovesicular membrane network. These affects appear to be independent of clofibrate's ability to stimulate the PP-activated receptor (PPAR) alpha pathway because other PPAR stimulators (DEHP, WY-14643) did not alter the Golgi complex or induce retrograde trafficking. These data suggest that PPAR alpha-independent, clofibrate-sensitive proteins participate in regulating Golgi-to-ER retrograde membrane transport, and, equally importantly, that clofibrate may be used as a pharmacological tool for investigating Golgi membrane dynamics.

Animals↗
PubMed1979

Differential effect of clofibrate on inflammation-induced alterations in plasma proteins in the rat.

Daily intramuscular injections of clofibrate begun 6h before the initiation of inflammation induced by the subcutaneous injection of turpentine exerted a differential, dose-dependent inhibition of the anticipated acute-phase globulin response. Specifically, clofibrate at 140mg/kg muted the increase in alpha(2)-macrofoetoprotein, but did not affect that of seromucoid or haptoglobin and only transiently inhibited the rise in copper and the rebound in transferrin. A higher dose, 280mg/kg, markedly suppressed alpha(2)-macrofoetoprotein appearance and the rebound in transferrin, somewhat inhibited the increase in seromucoid and haptoglobin and only transiently affected the rise in plasma copper; 420mg of clofibrate/kg very nearly abolished the appearance of alpha(2)-macrofoetoprotein, markedly suppressed the transferrin rebound and the increases in seromucoid and haptoglobin and again only transiently affected the increase in copper. Clofibrate did not diminish the localized inflammatory response, did not cause microscopically detectable liver damage and did not prevent the hypozincaemia, hypoalbuminaemia and enhanced amino acid uptake by liver usually associated with inflammation. Thus it is unlikely that clofibrate exerted its dose-dependent selective inhibition by muting the initial stimulus or by impairing hepatic metabolism. This seemingly selective action of clofibrate on plasma-protein alterations during inflammation may provide a means of elucidating the function of individual acute-phase globulin during disease. Clofibrate of itself, apart from inflammation, produced decreases in plasma zinc, copper, transferrin and seromucoid and an increase in hepatic amino acid uptake that were to some extent dependent on the dose of the drug.

Amino Acids↗
PubMed1979

Clofibrate-induced increase in coenzyme A concentration in rat tissues.

1. When clofibrate [ethyl 2-(4-chlorophenoxy)-2-methylpropionate] was administered subcutaneously to rats (600mg/kg per day for 5 days), the concentration of CoA and its acyl derivatives increased in several tissues. The increase in total CoA was 3.2-fold in the liver, 1.8-fold in the kidney, 2.7-fold in the heart and 2.4-fold in skeletal muscle. 2. To study the mechanism of this phenomenon, clofibrate-treated rats were injected with [(3)H]pantothenate intracardially and killed after 15min, 30min, 1 and 2h and 1, 3, 5 and 7 days for the determination of the incorporation of radioactivity into CoA and its precursors. Incorporation into CoA after 2h was 6.2-fold in the liver as compared with the control values and 4.6-fold in the kidneys. 3. The disappearance of the label from CoA was very slow compared with the rate of incorporation; it exhibited exponential kinetics, and was slower in the livers of the clofibrate-treated rats (t((1/2)) 18.2 days) than in the controls (t((1/2)) 5.6 days). 4. The rate of CoA degradation, calculated from the calculated rate constants of the apparent first-order kinetics of the disappearance of the label and from the CoA pool sizes, was approximately the same in the clofibrate-treated animals (11.5pmol/min per g), and the controls (11.6pmol/min per g). 5. These rates of CoA degradation indicate that the effect of clofibrate on CoA concentration may be mainly due to inhibition of the enzymes of CoA degradation, although recycling of the label cannot be excluded. The increase in the rate of pantothenate incorporation into CoA suggests that clofibrate also increases the synthesis of CoA.

Animals↗
PubMed1985

Protection of rats by clofibrate against the hypoglycaemic and toxic effects of hypoglycin and pent-4-enoate. An ultrastructural and biochemical study.

An ultrastructural and biochemical study of the toxic and hypoglycaemic effects of hypoglycin and pent-4-enoate was made on the livers of normal and clofibrate-fed rats. Injection of hypoglycin to rats doubles (from 22% to 44%) the volume fraction of mitochondria and decreases (from 1.05% to 0.26%) the volume fraction of peroxisomes in hepatocytes. The fast-acting toxin pent-4-enoate causes few ultrastructural changes except for the accumulation of lipids. In male adult rats fed with 0.5% clofibrate in their diet for 1-2 months, the volume fraction occupied by peroxisomes and mitochondria in hepatocytes rose to 6.26% and 29.5% respectively. Clofibrate feeding apparently protected the animals against the toxic, hypoglycaemic and hypothermic effects of hypoglycin and of pent-4-enoate, and completely prevented the ultrastructural damage caused by hypoglycin. After hypoglycin administration, hepatic mitochondrial butyryl-CoA dehydrogenase activity was inhibited by more than 90% and, surprisingly, the activity of the peroxisomal enzymes studied was largely preserved. When hypoglycin was given to rats fed on a clofibrate-containing diet, the oxidation of decanoylcarnitine, which was incomplete after hypoglycin treatment alone, remained incomplete with uncoupled mitochondria, but became apparently complete with coupled mitochondria. In the latter condition, there was a slowing of the rate during the last quarter of the pulse of oxygen uptake. Further, butyryl-CoA dehydrogenase activity was much less affected by hypoglycin in clofibrate-fed animals. Pent-4-enoate does not inhibit beta-oxidation in coupled mitochondria from clofibrate-treated rats.

Animals↗
PubMed2003

Characterization and cDNA cloning of a clofibrate-inducible microsomal epoxide hydrolase in Drosophila melanogaster.

In order to understand the roles of the epoxide hydrolases (EHs) in xenobiotic biotransformation in insects, we examined the induction of EHs by exogenous compounds in Drosophila melanogaster third instar larvae. Among the chemicals tested, clofibrate, a phenoxyacetate hypolipidermics drug, increased EH activity towards cis-stilbene oxide approximately twofold in larval whole-body homogenates. The same dose of clofibrate also induced glutathione S-transferase activity. The effect of clofibrate on EH induction was dose-dependent and the highest activity occurred with a 10% clofibrate application. Three other substrates conventionally used in EH assays (trans-stilbene oxide, trans-diphenylpropene oxide and juvenile hormone III) were poorly hydrolysed by larval homogenates, with or without clofibrate administration. Because the increased EH activity was localized predominantly in the microsomal fraction, we synthesized degenerate oligonucleotide primers with sequences corresponding to conserved regions of known microsome EHs from mammals and insects in order to isolate the gene. The 1597 bp putative cDNA of D. melanogaster microsomal EH (DmEH) obtained from a larval cDNA library encoded 463 amino acids in an open reading frame. Northern blot analysis showed that the transcription of DmEH was increased in larvae within 5 h of clofibrate treatment. Recombinant DmEH expressed in baculovirus hydrolysed cis-stilbene oxide (23 nmol.min-1.mg protein-1) and was located mainly in the microsomal fraction of virus-infected Sf9 cells. There was no detectable EH activity toward juvenile hormone III. These observations suggest that DmEH is involved in xenobiotic biotransformation, but not in juvenile hormone metabolism, in D. melanogaster.

Amino Acid Sequence↗
PubMedDate not supplied

Evaluation of the carcinogenic potential of clofibrate in the p53+/- mouse.

This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to p53+/- heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+/- than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+/- mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+/- mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+/- mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.

Administration, Oral↗
PubMed1980

Comparative ultrastructural study of rat hepatocytes after treatment with the hypolipidemic agents probucol, clofibrate, and fenofibrate.

Experimental findings are reported for two similarly conducted studies. One was designed to compared rat liver cell ultrastructure during and after 91 d of dosing with probucol, a hypocholesterolemic agent, and clofibrate, a hypolipidemic drug known to elicit marked alteration of rat hepatocellular morphology. The second was designed to similarly assess male rats after 28 d of treatment with the hypolipidemic agent fenofibrate. Diet mixes for these studies were prepared to attain dosage levels of approximately 500 mg/kg . d for probucol, 250 mg/kg . d for clofibrate, and 100 mg/kg . d for fenofibrate. Control rats were given untreated basal ration. Weekly adjustments in dietary concentrations were made in accordance with group mean food consumption and body weight changes. Probucol and clofibrate treatments produced statistically significant reductions in mean serum cholesterol levels of both sexes after 28 and 91 d of dosing. Only male rats were given fenofibrate, and they exhibited statistically significant cholesterol reductions after 28 d. Clofibrate and fenofibrate administration resulted in marked increases in liver weight/body weight ratios. Probucol had no statistically significant effects on liver weight/body weight ratios after 28 and 91 consecutive days of treatment. Light microscopy of liver sections stained with hematoxylin and eosin revealed an abnormal amount of cytoplasmic granularity within hepatocytes from rats given clofibrate and fenofibrate. The granules were identified by electron microscopy and cytochemistry as enlarged, proliferated peroxisomes--a known rat hepatocellular response to treatment with many hypolipidemic drugs. In addition, ultrastructural cytochemistry suggested reduced amounts of catalase in individual peroxisomes after clofibrate and fenofibrate dosing. Liver tissue from rats given probucol showed no abnormal cytoplasmic granularity and, ultrastructurally, no peroxisomal changes. Liver tissues from probucol-treated rats revealed features similar to those encountered in tissues from untreated control animals. It was concluded that the hypocholesterolemic response elicited by probucol treatment does not involve significant changes in rat liver cell morphology.

Animals↗