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PubMed1992

Fat intake and clofibrate administration have interrelated effects on liver cholesterol concentration and serum butyryl cholinesterase activity in rats.

Rats were fed for 15 d purified diets with different amounts of coconut fat, and with or without clofibrate. Fat was added at the expense of an isoenergetic amount of glucose. The hypolipidemic action of clofibrate was not influenced by the amount of fat in the diet. Clofibrate did not affect liver cholesterol concentration in rats fed the low fat diet, but it counteracted the rise in liver cholesterol seen in rats fed the high fat diet. This could relate to the observed raised intestinal clofibrate-hydrolyzing activity of rats fed the high fat diet, because hydrolysis of clofibrate gives rise to its biologically active form. In rats fed the low fat diet, but not in those fed the high fat diet, clofibrate raised the activity of serum esterase-1, which (unlike esterase-2) does not hydrolyze clofibrate. Possibly, the dramatic stimulatory effect of fat feeding on serum esterase-1 activity had overruled any influence of clofibrate. Clofibrate elevated serum butyryl cholinesterase activity, with this effect being amplified by fat feeding. High levels of dietary fat in the absence of dietary clofibrate did not alter serum butyryl cholinesterase activity. Clofibrate did not change butyryl cholinesterase and esterase-1 activities in small intestine. The high fat diet caused slightly higher levels of butyryl cholinesterase activity in small intestine, but markedly raised intestinal esterase-1 activity. This study shows that certain effects of clofibrate and a high fat diet are interrelated.

Animals↗
PubMed1982

Hypolipidemic and glycogenolytic effect of clofibrate (CPIB) in hypothyroid mice: role of insulin and glucagon.

1. The role of endogenous glucagon and insulin on the hypolipidemic and glycogenolytic effect of clofibrate was determined in the euthyroid and propylthiouracil (PTU)-induced hypothyroid mice. 2. PTU was fed in diet (0.15%) for 2 weeks and then clofibrate added to diet (0.25%) for 4 weeks. 3. Both PTU and clofibrate significantly increased liver weight but had no effect on kidney weight. PTU significantly decreased plasma triglycerides (TG) and increased cholesterol (Ch). 4. Clofibrate had a significant hypotriglyceridemic effect in both euthyroid and hypothyroid mice but did not affect plasma cholesterol. 5. Clofibrate decreased hepatic glycogen in euthyroid but not in hypothyroid mice. 6. Glucose-6-phosphatase activity was not affected by either PTU or clofibrate. 7. Neither PTU nor clofibrate affected hepatic TG or Ch. 8. Biliary lipid changes due to PTU treatment were reversed by clofibrate administration. 9. Since plasma insulin and glucagon levels were not affected by clofibrate in either euthyroid or hypothyroid mice, our results suggest that the hypotriglyceridemic and glycogenolytic effect of clofibrate is not mediated by changes in circulating insulin and glucagon ratio. 10. Moreover, while the glycogenolytic effect of clofibrate seems to be dependent, the hypotriglyceridemic effect seems to be independent of thyroid hormones.

Animals↗
PubMed1973

Clofibrate-induced antidiuresis.

Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.

Adult↗
PubMed1983

Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle.

Although clofibric acid is cleared predominantly by formation of an ester glucuronide, its plasma clearance is reduced in renal dysfunction. The mechanism of this phenomenon has been investigated in rabbits in which uranyl nitrate administration (0.0625-0.5 mg/kg) produced a dose-dependent decrease in creatinine clearance and clofibric acid plasma clearance. Uranyl nitrate doses of 0.3 mg/kg reduced creatinine clearance by approximately 90%, clofibric acid plasma clearance by approximately 60%, clofibric acid glucuronide renal clearance by approximately 85% and increased the time averaged plasma concentration of clofibric acid glucuronide approximately by 6-fold, compared to control values. Fifty percent of administered clofibric acid glucuronide is hydrolyzed to clofibric acid in rabbits with normal renal function. These studies support a mechanism for the renal function dependent plasma clearance of clofibric acid involving a futile cycle in which the net plasma clearance of clofibric acid is determined by the conjugation of clofibric acid and competition between renal clearance and hydrolysis of the ester glucuronide.

Acute Kidney Injury↗
PubMed1991

In vivo covalent binding of clofibric acid to human plasma proteins and rat liver proteins.

Recent studies have shown that acyl-glucuronide conjugates are chemically reactive electrophilic metabolites that can undergo transacylation reactions resulting in intra-molecular rearrangement, hydrolysis and covalent binding of aglycone to albumin both in vitro and in vivo. The hypolipidaemic agent clofibrate is eliminated almost entirely as clofibric acid glucuronide in humans and rats. The formation of clofibric acid-protein adducts was investigated in 14 patients receiving 0.5-2.0 g/day of clofibrate for hypercholesterolaemia, and in liver homogenates from 20 rats administered 280 mg/kg/day of clofibric acid for up to 21 days. Total clofibric acid concentrations in the patients ranged from 0 to 114 mg/L. Covalently bound clofibric acid-protein adducts were detected in all patients, even in one subject in whom there was no measurable plasma clofibric acid. Concentrations ranged from 2.2 to 53.4 ng/mg protein and, in eight patients receiving 1.0 g/day of clofibrate, were correlated (P less than 0.05) with renal function as assessed by creatinine clearance. Clofibric acid-protein adducts were also present in rat liver homogenates, and increased with increasing duration of treatment (P less than 0.0001), from a mean (SE) of 10.1 (0.7) to 32.3 (1.6) ng/mg protein. The covalent binding of drugs to tissue macromolecules has traditionally been associated with toxicity. Further research is required to elucidate the role of acyl-glucuronide conjugates in the formation of drug-protein adducts and their biological consequences.

Animals↗
PubMed1993

Induction of cytochrome P450 and peroxisomal enzymes by clofibric acid in vivo and in vitro.

We have analysed the induction of microsomal and peroxisomal proteins and their RNAs after treatment of hepatocytes with the peroxisome proliferator, clofibric acid, in vitro and in vivo. After treatment of hepatocytes with 1 mM clofibric acid for 4 days, P450 4A1 RNA is induced 500-fold, and acyl-CoA oxidase and P450 2B1 280-fold, relative to control cultures. These RNAs are detectably induced after administration of 25 microM clofibric acid, and show a similar induction response with increasing doses of clofibric acid. Western blot analysis of the P450 4A and bifunctional enzyme (BFE) proteins showed that both were induced in parallel with increasing doses of clofibric acid, over a range of 25 microM-1 mM. The distribution of the induced proteins was examined by immunocytochemistry. Increasing doses of clofibric acid led to an increase in the average intensity of staining for both proteins throughout the hepatocyte population. There was, however, a graded variation between hepatocytes in the intensity of staining, both for P450 4A and BFE proteins. The heterogeneity in response of the hepatocyte population in vitro may be related to differential sensitivity of hepatocytes to induction in vivo. Therefore, rats were dosed with 0, 50 or 300 mg/kg of clofibric acid for 4 days by gavage, and the livers were examined by immunocytochemistry. After 50 mg/kg of clofibric acid, both P450 4A and BFE were induced mainly in zones 3 and 2 of the liver acinus. However, after 300 mg/kg of clofibric acid, staining for both proteins was strong and homogenous throughout the liver acinus. Thus, hepatocytes from zones 3 and 2 of the acinus are differentially responsive to induction by clofibric acid.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1996

NAD+ biosynthesis and metabolic fluxes of tryptophan in hepatocytes isolated from rats fed a clofibrate-containing diet.

Hepatocytes were isolated from rats fed a diet with or without 0.25% clofibrate, and NAD+ synthesis by the hepatocytes was determined using either [carboxyl-14C]nicotinic acid or [5-3H]tryptophan. NAD+ and total pyridine nucleotides synthesized from [14C]nicotinic acid by the clofibrate-treated cells were not significantly different from those synthesized by the control cells when expressed on the basis of nanomoles per hour per milligram of DNA. On the contrary, NAD+ synthesized from [3H]tryptophan was significantly higher in the clofibrate-treated cells (158% of the control cells) on the basis of nanomoles per hour per milligram of DNA. Clofibrate was inhibitory to tryptophan metabolism as a whole, affecting the glutarate pathway more (decreased to 37% of control) than the kynureninase flux (decreased to 64% of control). As a result, the quinolinate-NAD flux, estimated as the difference in the amounts of tryptophan metabolized by the two metabolic pathways, increased in the clofibrate-treated hepatocytes. The increase in quinolinate during the incubation was 8 times more in the clofibrate-treated cells than in the control cells, which confirmed alteration in the metabolic fluxes of tryptophan in the clofibrate-treated cells. Hepatic quinolinate phosphoribosyltransferase (EC 2.4.2.19) activity increased with dietary clofibrate and returned to the control level 1 week after removing clofibrate from the diet. Nicotinate phosphoribosyltransferase (EC 2.4.2.11) and NAD+ glycohydrolase (EC 3.2.2.5) activities remained unchanged with dietary clofibrate.

Animals↗
PubMedDate not supplied

Lifetime prolongation in voluntary alcohol-consuming rats (SHR) treated with clofibrate.

Clofibrate affects lipid and alcohol as well as drug and eicosanoid metabolism. Spontaneous hypertensive rats (SHR) further increase their high voluntary alcohol consumption during clofibrate feeding. The interaction of alcohol and clofibrate was studied in two long-term trials. Seventy-nine male SHR (aged 27 weeks) were offered increasing concentrations of ethanol, up to 30% (tap water ad lib), and 3 months later 0.5% clofibrate-food. Four groups were established: N, normal controls; NA, standard diet+alcohol; C, clofibrate feeding; and CA, clofibrate feeding + alcohol. Food intake, alcohol consumption, body weight, and laboratory values were recorded continuously. Life duration (weeks) after the start of the trial was 63.3 +/- 3.3 in N, 73 +/- 2.6 in NA, 77.7 +/- 4.3 in C, and 90.3 +/- 2.8 in CA. There were no alcohol-related liver findings in NA and CA. Most of the animals died of cardiac and renal failure. An increase of tumors in clofibrate-treated rats was not observed. Voluntary alcohol consumption or clofibrate feeding significantly lengthens lifetime, which is prolonged by 42% if ethanol is combined with clofibrate. This is obviously not mediated by the lipid lowering effect or an influence on body weight and blood pressure of either clofibrate or alcohol.

Alcohol Drinking↗
PubMed1996

Increased conversion ratio of tryptophan to niacin by the administration of clofibrate, a hypolipidemic drug, to rats.

The effect of clofibrate, a hypolipidemic drug and also known as a peroxisomal proliferator, on the conversion ratio of tryptophan to niacin was investigated by using rats. The rats were fed with a nicotinic acid-free, 20% casein diet (control group) or the same diet + 0.25% clofibrate group) for 19 days. The conversion ratio gradually increased with increasing number of days. Around day 8, the ratio was about 10-times higher in the clofibrate group than in the control group, and the value remained almost constant after that day. The content of liver total nicotinamide was higher in the clofibrate group than in the control group. Among the enzymes involved in the conversion of tryptophan to niacin, the aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) activity, which is critical in the conversion, was lower in the clofibrate group than in the control group. As the change in ACMSDase activity took several days, there is a possibility that clofibrate decreased the biosynthesis of ACMSDase protein and/or mRNA. To learn whether the increase in the conversion ratio by clofibrate would be nutritionally meaningful or not, the growth-promoting activity of clofibrate was determined by using weanling rats fed with a nicotinic acid-free, tryptophan-limiting diet (basal diet). As a result, the body weight gain was higher in the clofibrate group than in the basal group. This result shows that clofibrate enhanced the conversion ratio without any side-effects under the conditions used and supports again the claim that the activity of ACMSDase exerts a critical influence on the tryptophan-NAD conversion.

Animals↗
PubMed1971

Ischaemic heart disease: a secondary prevention trial using clofibrate. Report by a research committee of the Scottish Society of Physicians.

A trial is reported of the effects of giving clofibrate to prevent progression of pre-existing ischaemic heart disease. There were two groups randomly distributed between clofibrate (350 patients) and placebo (367 patients) regimens. The trial lasted about six years and was conducted in 19 hospitals in Scotland. The criteria of acceptance into the trial were precise and were monitored by one observer. The standards of diagnosis of events were defined and all protocols and electrocardiograms were read blind by one observer.THREE CATEGORIES OF PATIENTS WERE ADMISSIBLE TO THE TRIAL: (1) patients with one myocardial infarction (W.H.O. E.C.G. criteria) between 8 and 16 weeks before the start of the trial; (2) patients with angina of a duration of 3 to 24 months, provided their E.C.G. showed signs of myocardial ischaemia at rest or after exercise; and (3) patients with one recent myocardial infarction and pre-existing angina as defined above.There were fewer deaths in patients with angina (categories 2 and 3 above) treated with clofibrate than in those on placebo. The mortality in the former group was reduced by 62%, and this is a statistically significant difference. Clofibrate did not have any statistically significant effect in reducing the rate of non-fatal infarction in patients with angina or in those with myocardial infarction and pre-existing angina, though a beneficial trend was evident when both subgroups were combined (a 44% reduction compared with the placebo group). There was a significant reduction in all events (fatal and non-fatal) in patients with angina ("all anginas") in the clofibrate-treated group; the rate was reduced by 53%.Clofibrate did not alter the overall mortality or morbidity rates in patients admitted to the trial with recent myocardial infarction without preceding angina of more than three months' duration. In one subgroup there was a statistically significant adverse effect in the clofibrate-treated group. The lack of any overall effect in patients with myocardial infarction might be related to the unexpectedly low mortality rate (2.97%) in the placebo group; it is usually in the region of 4-9% per annum after first myocardial infarction.In patients categorized as "all anginas" there was significant reduction in events whether the initial serum cholesterol level was high (greater than 260 mg/100 ml) or normal. Clofibrate seemed to have a small but not significant beneficial effect in patients with myocardial infarction with initially high serum cholesterol levels, but was of no value in those with initially normal serum cholesterol levels. There was no significant relationship between the response or lack of response of serum cholesterol to clofibrate and the incidence of events either in patients with angina or in those with infarction.The main conclusion of this trial is that clofibrate had a beneficial effect in reducing mortality and, to a lesser extent, morbidity in patients who presented with angina ("all anginas"). This effect was independent of initial serum cholesterol levels or the extent to which serum cholesterol was lowered. The drug had no significant overall effect on prognosis in patients with myocardial infarction alone.

Adult↗
PubMed1980

[Effect of etofylline clofibrate on the composition of lipoproteins in hyperlipidaemia type IIb and IV (author's transl)].

Efficacy of 1-(theophyllin-7-yl)-ethyl-2[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, Duolip) (3 x 250 mg) was evaluated in a double-blind cross-over study in 20 patients of type 11b (10 and type IV (10) in comparison to a commercial drug combination (= standard preparation) of clofibrate (3 x 500 mg) and beta-pyridylcarbinol hydrogentartrate (3 x 25 mg). This standard preparation was known from clinical results to be superior over clofibrate in antilipaemic potency. All patients had been already on a diet for several months and in majority were additionally treated with antihyperlipaemic drugs. The treatment periods lasted over 8 weeks each. They were introduced by placebo phases of 4 weeks duration. Between the treatment periods with etofylline clofibrate and with the standard preparation, placebo phases of 4 weeks were inserted, too. The results indicate, that between etofylline clofibrate and the standard preparation there are no remarkable differences and thus 750 mg etofylline clofibrate correspond to 1500 mg clofibrate combined with 75 mg beta-pyridylcarbinol hydrogentartrate in their efficiencies. Since the clofibric acid proportion of etofylline clofibrate clinically is known as ineffective we postulate a potentiation of its effect by its metabolits to cause this surprising effect. In type IIb the cholesterol was distinctly decreased in the VLDL-fraction by 22% and significantly increased in the HDL-fraction by 22%. In type IV triglycerides and cholesterol dropped in the VLDL by 11% and 16%, resp., unless the LDL-fraction revealed an increase of the lipid content. The lipids of the HDL-fraction did not show any essential alternations. Side effects were not observed. The investigations prove that etofylline clofibrate is suitable for the treatment of hyperlipoproteinaemia with elevated triglycerides and cholesterol.

Adult↗
PubMed1983

Hepatic microsomal glucuronidation of clofibric acid in the adult and neonate albino rat.

Hepatic microsomal UDP glucuronyltransferase activity towards the acid substrate clofibric acid has been described in the adult and neonate albino rat. The enzyme was maximally activated, approximately 2-fold, in the presence of 0.1-0.4% (w/v) digitonin. Induction of the digitonin activated clofibric acid glucuronyltransferase was observed following phenobarbitone treatment in vivo (2.2-fold), and to a lesser extent, following beta-naphthoflavone treatment (1.3-fold). Clofibrate treatment in vivo (of which clofibric acid is the ester hydrolysis product) had no effect on clofibric acid glucuronidation in vitro. The activity of clofibric acid glucuronyltransferase in the liver of rat before and at birth was low (approx. 0.08 nmoles glucuronide formed/min/mg microsomal protein). The activity increased 5-fold during the first three post-natal days. After this time, the activity increased linearly reaching adult levels by four weeks after birth. The data indicated that clofibric acid glucuronyltransferase belongs to the neonatal cluster of enzymes and clofibric acid is a group 2 substrate. Clofibric acid, a common therapeutic agent, is a useful, acid substrate for the estimation of mammalian hepatic microsomal glucuronyltransferase activity.

Aging↗
PubMed1980

Branched chain amino acid oxidation in cultured rat skeletal muscle cells. Selective inhibition by clofibric acid.

Leucine metabolism in skeletal muscle is linked to protein turnover. Since clofibrate is known both to cause myopathy and to decrease muscle protein content, the present investigations were designed to examine the effects of acute clofibrate treatment on leucine oxidation. Rat skeletal muscle cells in tissue culture were used in these studies because cultivated skeletal muscle cells, like muscle in vivo, have been shown to actively utilize branched chain amino acids and to produce alanine. The conversion of [1-(14)C]leucine to (14)CO(2) or to the [1-(14)C]keto-acid of leucine (alpha-keto-isocaproate) was linear for at least 2 h of incubation; the production of (14)CO(2) from [1-(14)C]leucine was saturable with a K(m) = 6.3 mM and a maximum oxidation rate (V(max)) = 31 nmol/mg protein per 120 min. Clofibric acid selectively inhibited the oxidation of [1-(14)C]leucine (K(i) = 0.85 mM) and [U-(14)C]isoleucine, but had no effect on the oxidation of [U-(14)C]glutamate, -alanine, -lactate, or -palmitate. The inhibition of [1-(14)C]leucine oxidation by clofibrate was also observed in the rat quarter-diaphragm preparation. Clofibrate primarily inhibited the production of (14)CO(2) and had relatively little effect on the production of [1-(14)C]keto-acid of leucine. A physiological concentration-3.0 g/100 ml-of albumin, which actively binds clofibric acid, inhibited but did not abolish the effects of a 2-mM concentration of clofibric acid on leucine oxidation. Clofibrate treatment stimulated the net consumption of pyruvate, and inhibited the net production of alanine. The drug also increased the cytosolic NADH/NAD(+) ratio as reflected by an increase in the lactate/pyruvate ratio, in association with a decrease in cell aspartate levels. The changes in pyruvate metabolism and cell redox state induced by the drug were delayed compared with the nearly immediate inhibition of leucine oxidation. These studies suggest that clofibric acid, in concentrations that approximate high therapeutic levels of the drug, selectively inhibits branched chain amino acid oxidation, possibly at the level of the branched chain keto-acid dehydrogenase.

Amino Acids, Branched-Chain↗
PubMed1995

The effects of probucol and clofibrate alone and in combination on hepatic cholesterol metabolism in the male rat.

Male rats were fed for 10 days on a diet supplemented with either probucol or clofibrate, alone or in combination, and the effects of the drugs on hepatic cholesterol metabolism studied. Plasma triacylglycerols were significantly lowered (15.6%, P < 0.05) by the drugs in combination but not individually whereas plasma cholesterol levels were reduced by probucol alone (22.4%, P < 0.05) and the combined treatment effected a further decrease leading to a total reduction of 50.6% (P < 0.001). Probucol reduced hepatic cellular triacylglycerols (20.0%, P < 0.05) and cholesterol (15.3%, P < 0.05) but cholesteryl esters were unaffected. In combination with clofibrate, probucol accentuated the reductions in both cellular cholesterol and cholesteryl esters produced by clofibrate alone and lowered their levels by 22.8%, P < 0.01 and 38.5%, P < 0.001, respectively. Although probucol, on its own, did not affect the activity of acyl-coenzyme A:cholesterol acyltransferase (ACAT), its combination with clofibrate caused less inhibition (43.5%, P < 0.01) of this enzyme activity than clofibrate alone (65.7%, P < 0.001). Probucol had a similarly moderating effect on the clofibrate-induced reductions in microsomal cholesterol and cholesteryl esters. Neither the microsomal nor the cytosolic neutral cholesteryl ester hydrolase was affected by probucol alone although both enzymes were dramatically increased (between 350% and 550%) by clofibrate and the combined treatment. The activity of the hepatic cytosolic inhibitor of cholesteryl ester hydrolase was unaffected by clofibrate or probucol individually but the two drugs in combination increased the total activity of the inhibitor by 52.1%, P < 0.01. When allowance was made for this increased inhibitor activity, it was clear that probucol accentuated the stimulatory effect of clofibrate on the cytosolic nCEH.

Animals↗
PubMed1984

Influence of clofibrate on thyroid hormone and muscle protein turnover.

Clofibrate, a hypolipidemic agent, has been shown to increase muscle protein degradation. The possible role of thyroid hormones in this phenomena was examined. Clofibrate treatment of rats for 2 weeks resulted in a significant decrease in total thyroxine and triiodothyronine levels in serum. Reverse T3 and resin uptake values remained unchanged. When exogenous thyroxine was co-administered with clofibrate, serum TSH levels were suppressed, but the increased muscle protein degradation was not reversed. Equilibrium dialysis and Scatchard analysis of the binding of 125I-thyroxine to serum proteins indicated that clofibrate competitively inhibits the binding of thyroid hormone to serum proteins by decreasing its apparent binding affinity. In the presence of lower total thyroid hormone concentrations and an elevated free thyroxine fraction, the total free hormone levels are estimated to be in the normal range in the serum of clofibrate treated rats. Clofibrate seems to act like thyroid hormone since it binds to and displaces T4 from plasma proteins. Because free thyroid hormone levels are in the normal range, the thyroid hormone-like effects of clofibrate on the cell may be additive to the T4 effects, and are probably responsible for the hypermetabolic state seen in the muscle of clofibrate-treated animals. Our data suggest that the effects of clofibrate in muscle are complex. In addition to competitively altering the binding of thyroxine to serum proteins, this substance may also exert a hitherto unrecognized thyroid-hormone-like subcellular effect resulting in increased muscle protein degradation, and in augmented ouabain-sensitive ATPase activities.

Animals↗
PubMed1994

Role of testosterone in the induction of hepatic peroxisome proliferation by clofibrate.

Hepatic peroxisome proliferation is induced by a number of agents, including clofibrate. Sustained proliferation of peroxisomes is associated with the development of hepatocellular carcinoma. In the present study, we have investigated the role of testosterone in peroxisome proliferation induced by clofibrate. Three groups of male rats (intact, castrated, and castrated replaced with testosterone) were studied. Proliferation of peroxisomes was induced by feeding clofibrate (0.25%, 0.50%, and 1.0% of diet) for 2 weeks. Peroxisome proliferation was monitored by measuring total peroxisomal beta-oxidation activity. In intact rats, the peroxisomal beta-oxidation activity (nmol/min/mg protein) increased in a dose-dependent manner and was 7.2 +/- 0.4, 52.6 +/- 7.5, 63.2 +/- 3.7, and 92.4 +/- 4.0 at clofibrate doses of 0%, 0.25%, 0.50%, and 1.0%, respectively. In contrast, in castrated rats, the total peroxisomal beta-oxidation activity was significantly (P < .01) lower at clofibrate levels of 0.25% and 0.50% (25.8 +/- 2.7 and 42.5 +/- 2.2, respectively), but not at the clofibrate level of 1.0% (85.0 +/- 6.3). Testosterone replacement of castrated rats restored the peroxisomal beta-oxidation activity. To determine whether the above results were related to the metabolism of clofibrate in the absence or presence of testosterone, we measured serum clofibrate levels. These levels were 50% lower in castrated rats than in intact rats or in testosterone-treated castrated rats. The activity of hepatic uridine diphosphate (UDP)-glucuronyltransferase, the enzyme catalyzing the glucuronidation of clofibrate, was measured using either bilirubin or 4-methylumbelliferone as substrates and was found to be unaffected by castration or testosterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Enhancement of voluntary alcohol consumption in rats by clofibrate feeding.

Clofibrate is known to be an inducer of alcohol- and acetaldehyde dehydrogenase. Therefore, male rats were offered increasing amounts of alcohol over a period of three months. Eventually they could choose between a 30% alcohol solution and tap water which was available ad lib. Animals were sacrificed after further 1 1/2 months of clofibrate feeding. Before clofibrate feeding voluntary intake of alcohol was 3.47 g/kg per day and increased up to 7.77 g/kg per day, i.e., by 123% within the clofibrate feeding period while the alcohol intake of controls increased from 3.84 to 4.88 g/kg per day, i.e., by only 27%. Food consumption increased in the clofibrate control group, whereas in the alcohol drinking clofibrate group the total caloric intake increase was due mainly to the enhancement of alcohol consumption. Relative liver weight was increased by clofibrate in the non-drinking as well as in the drinking group by 59%. Measurements of triglycerides and cholesterol exhibited changes typical for clofibrate in ethanol drinking and non-drinking animals. Probably the clofibrate-alcohol interaction results in accelerated ethanol metabolism and increased metabolic tolerance by induction of the ethanol detoxifying system in the liver.

Acetaldehyde↗
PubMed1997

Clofibrate feeding to Sprague-Dawley rats increases endogenous biosynthesis of oxalate and causes hyperoxaluria.

The effects of clofibrate feeding (5 g/kg diet) on oxalate metabolism were investigated in male and female rats. Following clofibrate feeding, 24-hour urinary excretion of oxalate increased until 4 days and then reached a plateau. Whereas the contribution of dietary oxalate (1.4 g/kg diet, as potassium salt) to urinary oxalate was less than 5% in both control and clofibrate-treated male rats, the contribution of dietary glycolate (1.0 g/kg diet, as sodium salt) to urinary oxalate was six times higher in clofibrate-treated male rats compared with controls, indicating that the clofibrate-induced hyperoxaluria is due to increased endogenous biosynthesis of oxalate. This was supported by the increased lactate dehydrogenase (LDH) activity observed in liver supernatants of clofibrate-treated rats compared with controls, and the increased rate of conversion of glycolate and glyoxylate to oxalate by clofibrate-treated male rat liver supernatants. Female rats had lower excretion of urinary oxalate and lower levels of liver glycolic acid oxidase (GAO) as compared with males. Clofibrate-treated female rat liver supernatants had higher LDH levels and produced more oxalate from glyoxylate. Thus, it can be concluded that the increase in LDH activity may be the cause of the increased endogenous biosynthesis of oxalate leading to increased urinary excretion of oxalate in male and female rats treated with clofibrate.

Alcohol Oxidoreductases↗