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PubMedDate not supplied

[Cortisol inhibition of cholesterol and phospholipid biosynthesis in the rat liver].

Effect of hydrocortisone on biosynthesis of cholesterol and phospholipids in liver tissue was studied using intact rats, in adrenalectomy, under conditions of stimulation of lipid biosynthesis by cholestyramine and Triton WR-1339. Hydrocortisone was shown to inhibit biosynthesis of cholesterol and phospholipids in rat liver tissue if 2-14C-acetate was used as a precursor. The hormone inhibited biosynthesis of lipid components in membranes of adrenalectomized rats. Under conditions of preactivation of the lipid biosynthesis, using simulation with cholestyramine and Trition WR-1339, hydrocortisone decreased the synthesis of cholesterol and phospholipids.

Adrenalectomy↗

PubMed1979

Postcholecystectomy diarrhea.

Diarrhea developed in three patients following cholecystectomy. Fecal bile-acid excretion was elevated in the two patients for whom it was measured. All three patients' diarrhea resolved with cholestyramine resin therapy. This experience suggests that gallbladder removal may lead to a bile-acid-mediated diarrhea in some patients, and that this condition appears to respond to cholestyramine therapy.

Bile Acids and Salts↗

PubMed1995

Effects of 2164U90 on ileal bile acid absorption and serum cholesterol in rats and mice.

2164U90, [(3R,5R)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4- benzothiazepine 1,1-dioxide], was found to be a potent inhibitor of the ileal bile acid active transport system. In vitro, 2164U90 decreased uptake and active transport of taurocholic acid by rat everted ileal sacs with IC50s of 4.0 microM and 1.5 microM, respectively. In vivo, 2164U90 produced dose-dependent increases in 23,25-75Se-labeled homocholic acid taurine (SeHCAT) fecal excretion in rats and mice at doses of 3-30 mg/kg and 1-10 mg/kg, respectively. In rats, 30 mg/kg 2164U90 was equivalent to 500 mg/kg cholestyramine. Two days oral administration of 10 mg/kg 2164U90 to rats decreased the bile concentrations of total bile acids 42%, orally administered [3H]taurocholic acid ([3H]TC) 82%, and cholesterol 35%. Cholestyramine (500 mg/kg) had effects similar to 2164U90 on total bile acid and orally administered [3H]TC concentrations but had no effect on biliary cholesterol. The hypocholesterolemic activity of 2164U90 was determined in cholesterol-cholic acid-fed rats and cholesterol-cholic acid-coconut oil-fed mice. 2164U90 inhibited the dietary-induced increase in dextran sulfate-precipitable lipoprotein cholesterol (VLDL+LDL) at doses comparable to doses needed to increase the fecal excretion of bile acids. These data indicate that 2164U90 decreases bile acid absorption by inhibiting the ileal bile acid active transport system, resulting in hypocholesterolemic activity.

Administration, Oral↗

PubMed1976

Sampling intestinal content with a sequestering capsule. A noninvasive technique for determining bile acid kinetics in man.

A noninvasive technique for determining bile acid kinetics by isotope dilution in man features the intravenous injection of a radiolabeled bile acid, together with daily oral administration, for several days, of capsules of dialysis membrane containing cholestyramine and colored beads for dating. The cholestyramine traps conjugated bile acids during transit of the small intestine. Capsules are recovered from stool by sieving, sequestered bile acid is eluted, conjugated bile acids are isolated chromatographically, and their specific activity is determined. The precision and validity of this sequestering capsule technique were assessed by comparing the specific activity decay curve of chenodeoxycholyl conjugates obtained from capsule samples with that obtained from duodenal samples in seven healthy volunteers in whom the bile acid pool had been labeled with [14C]chenodeoxycholic acid. Estimates of pool size by the two methods correlated well (r = 0.98), as did the daily fractional turnover rate (r = 0.96). The mean (+/-SD) percentage differences for the kinetic parameters of pool size (8.3 +/- 13.6), fractional turnover rate (-15.2 +/- 11.5), and synthesis rate (-4.3 +/- 11.4) were fairly small, indicating that the noninvasive method has validity. However, agreement between simultaneously administered capsules was only fair, especially when the amount of bile acid trapped was small, suggesting that the precision of the capsule technique may be less than that of the conventional duodenal sampling technique; the latter probably obtains a more valid sample of the bile acid pool.

Administration, Oral↗

PubMed1994

Isoprenoid biosynthesis in rat liver mitochondria. Studies on farnesyl pyrophosphate synthase and trans-prenyltransferase.

Mevalonate pathway enzyme activities in rat liver mitochondria were investigated, and it was found that isopentenyl pyrophosphate can be utilized for the synthesis of all-trans-polyprenyl pyrophosphates in vitro. In this reaction sequence intermediate formation of farnesyl pyrophosphate (FPP) predominates, and the FPP synthase activity was studied in more detail. The mitochondrial activity constitutes 13% of the total hepatic capacity for FPP synthesis, exceeding the corresponding microsomal, nuclear, and peroxisomal activities by 10-fold. Mitochondrial FPP synthase exhibits trypsin sensitivity only after sonication of intact mitochondria and upon subfractionation the activity is found localized in the matrix. FPP synthase activities at different locations responded distinctly when rats were treated with a diet enriched in cholesterol or containing mevinolin or cholestyramine. With the high cholesterol diet, mitochondrial FPP synthase activity increased 2-fold, while the cytosolic activity was slightly decreased. Both mevinolin and cholestyramine treatment resulted in 3-fold increases in cytosolic FPP synthase activities, without altering the mitochondrial activity. FPP was utilized as substrate for trans-prenyltransferase activity in the inner mitochondrial membrane. The products formed in this reaction were identified as nona- and decaprenyl-PP, and the reaction was influenced by changes in both substrate and Mg2+ concentration, giving more decaprenyl-PP when the concentrations of these substances were increased. These results demonstrate that mitochondria utilize endogenously produced FPP for isoprenoid biosynthesis and that the biosynthetic steps in mitochondria are regulated independently from those occurring in other subcellular compartments.

Animals↗

PubMed1995

Influence of dietary retrograded starch on the metabolism of neutral steroids and bile acids in rats.

Diets enriched in retrograded amylose (RS3) have been shown to lower serum cholesterol concentrations in rats. The possibility was tested that this hypocholesterolaemic effect of RS3 is caused by an increase in excretion of neutral steroids and/or bile acids. Six groups of ten rats were fed on purified diets containing either 12 or 140 g RS3/kg solid ingredients with and without added cholesterol (5g/kg). Low-RS3 diets, with and without added cholesterol, to which the bile-acid-binding resin cholestyramine (20 g/kg) was added, were used as reference. The high-RS3 diets v. the low-RS3 diets tended to reduce the increase in the total serum cholesterol concentration during the course of the experiment (P = 0.067), decreased serum triacylglycerol concentrations, raised total neutral steroids and total bile acids in caecal contents and faecal excretion of total bile acids, but lowered faecal excretion of neutral steroids. In addition, the serum concentration of total 3 alpha-bile acids was markedly raised by the high-RS3 diets. The high-RS3 diets raised the faecal excretion of lithocholic and muricholic acids, but lowered that of hyodeoxycholic acid, and increased the caecal amounts of lithocholic, ursodeoxycholic, beta-muricholic and omega-muricholic acids. Apart from the stimulation of faecal bile acids excretion, the effects of cholestyramine on bile acid metabolism differed at various points from those of RS3. Cholesterol feeding had predictable effects on cholesterol metabolism and led to greater elevating effects of RS3 on the faecal and caecal amounts of muricholic acids. The results suggest that the serum-cholesterol-lowering effect of high-RS3 diets may be explained by an increased influx of neutral steroids and bile acids into the caecum, and increased faecal excretion of bile acids, and/or by an altered intestinal bile acid profile.

Amylose↗

PubMed1996

Effects of hypolipidemic drugs on the expression of genes involved in high density lipoprotein metabolism in the rat.

Since plasma high density lipoprotein (HDL) concentrations are inversely related to the development of atherosclerosis, induction of HDL after pharmacological treatment is considered of benefit. To study whether currently used hypolipidemic drugs affect HDL metabolism by modulating the expression of genes involved in HDL metabolism, liver and intestinal apolipoprotein (apo) AI, apo-AII and apo-AIV gene expression was evaluated in rats treated with different classes of hypolipidemic drugs, and correlated to the changes in plasma lipid and apolipoprotein concentrations. In rats, the most pronounced hypolipidemic effects were observed after treatment with the fibrates clofibrate and fenofibrate, which lowered plasma lipid, apo-AI and apo-AIV concentrations. This decrease was accompanied by lowered liver apo-AI, apo-AII and apo-AIV mRNA levels. None of the other compounds tested affected plasma cholesterol, whereas probucol and simvastatin decreased plasma triglyceride concentrations. Apo-AI and apo-AII mRNA remained constant after nicotinic acid and probucol, whereas liver apo-AIV mRNA levels decreased. Cholestyramine increased hepatic apo-AI and apo-AII, but not apo-AIV mRNA levels. Simvastatin treatment increased apo-AI mRNA nearly threefold, whereas apo-AII and apo-AIV decreased by more than 50%. Similarly as after cholestyramine, the alteration in hepatic apo-AI mRNA levels did not result in changed plasma apo-AI concentrations. Remarkably, none of the drugs tested significantly affected intestinal apolipoprotein mRNA levels. These results indicate that hypolipidemic drugs may act on plasma lipoprotein metabolism by regulating apolipoprotein gene expression. Further studies in humans and primates are therefore warranted.

Actins↗

PubMed1995

Nutritional, metabolic, and genetic determinants of the progression of coronary heart disease. STARS Group.

The St. Thomas' Atherosclerosis Regression Study (STARS) showed that treatment of mild hypercholesterolemia with diet or diet plus cholestyramine favorably influences the course of coronary heart disease (CHD) over 3 years in middle-aged men. The study employed quantitative angiography to measure change in coronary luminal dimensions. Angiographic benefit was paralleled by improvement in clinical outcomes. The study allowed a detailed analysis of the nutritional, metabolic, and genetic determinants of the progression of CHD. Significant associations were found between changes in both focal and diffuse estimates of coronary atherosclerosis and the plasma concentrations of low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B, dietary intake at total and saturated fat, and polymorphisms of the apo-AI gene promoter region and angiotensin-converting enzyme (ACE) gene. Up to 38% of the variance in the progression of CHD could be explained by the independent effects of LDL cholesterol and dietary intake of saturated fat. The ACE genotype was only an independent predictor of the progression of CHD in patients whose LDL cholesterol had been substantially reduced with diet and cholestyramine. The clinical significance of the nutritional, metabolic and genetic findings is discussed.

Anticholesteremic Agents↗

PubMed1996

[New markers of atherogenic risk: hemorrheological profile in children and adolescents with familial hypercholesterolemia].

OBJECTIVE: Recent studies in adults have shown that hemorrheological alterations are predictive of early cardiovascular disease, but it is unknown if they are related to hyperlipemia or are secondary to an established atherosclerotic process and if they appear during childhood. PATIENTS AND METHODS: Several rheological parameters have been studied in 36 patients with familial hypercholesterolemia (FH). These patients were between 2 and 16 years of age and 12 of them were being treated with cholestyramine. Thirty-five controls (CG) were individually matched for age and sex. RESULTS: The FH patients treated with cholestyramine did not show significant differences in any of the six rheological parameters that were studied when compared to the other patients. Therefore, the results of the FH group were analyzed as a whole when they were compared with the CG. The following significant differences were found: Index of erythrocyte aggregation at stasis 5.0 +/- 1.2 vs 3.6 +/- 1.0 (p < 0.001), index of erythrocyte aggregation at low rate of blood shears 8.1 +/- 1.7 vs 6.9 +/- 1.4 (p < 0.001) and plasma viscosity 1.19 +/- 0.11 vs 1.16 +/- 0.04 mPA/s (p < 0.01). There were no significant differences in the plasma fibrinogen nor in the blood viscosity at shear rats of 230/s and 23/s. Carotic echo-doppler was taken in the HF patients which was normal, indicative of the absence of atherosclerosis lesions in the fibrous plaque phase. CONCLUSIONS: These results indicate that there are hemorrheological alterations in absences of established atherosclerotic lesions, which are associated with hypercholesterolemia and that emerge in the pediatric population. Therefore, research in FH patients offers new data to evaluate the atherogenic risk and its complications.

Adolescent↗

PubMed1977

[Drug treatment of hyperlipoproteinemias].

If by regulation of the ideal weight, by type-optimated diet and physical conditioning we do not succeed in a satisfying regulation of the hyperlipoproteinaemias, the indication to the medicamentous therapy is given. For the treatment of type IIa in the first place cholestyramine and essential phospholipids are taken into consideration, in unsatisfying effect the combination cholestyramin-regadrin. For the types IIb-V regadrin and preparations of nicotinic acid are the remedies of choice. In an unsatisfying decrease of lipids the combination regadrin-nicotinic acid and regadrin-buformin-respectively, should be used. To what extent by a medicamentous decrease of lipids a primary or secondary prevention of ischaemic vascular diseases is possible, at present cannot be answered definitively.

Cholestasis↗

PubMed1998

Modulation of cholesterol metabolism affects tumor growth in hamsters.

To investigate the effects of cholesterol and cholesterol-lowering agents on cholesterol metabolism and tumor growth, 0.5% cholesterol, 2% cholestyramine, or 0.01% simvastatin was fed to hamsters with transplanted Simian virus40 transformed tumor cells. Tumor weight, tissue cholesterol and DNA concentrations, and HMG-CoA reductase activities were determined. Cholesterol or cholestyramine feeding did not affect the tumor growth, however, the tumor weight and DNA concentration were decreased and tumor HMG-CoA reductase activity was increased in the simvastatin group. In conclusion, simvastatin may inhibit the DNA synthesis and growth of the Simian virus40 transformed tumor cells possibly through the inhibition of cholesterol and isoprenoids synthesis in the hamster.

Animals↗

PubMedDate not supplied

Treatment of persistent Pfiesteria-human illness syndrome.

Patients with exposure to Pfiesteria toxin have developed an illness, Pfiesteria-human illness syndrome, characterized by skin lesions, headache, myalgias, conjunctival irritation, bronchospasm, abdominal pain, secretory diarrhea, recent memory loss, and difficulties with number sequencing. Not all patients demonstrated all features of the syndrome. The natural history of Pfiesteria-human illness syndrome shows that most patients' symptoms improve without treatment. This article reports the improvement of symptoms that had persisted for over one month in five patients, which the author attributes to treatment with cholestyramine. These patients were self-referred to the Pocomoke River Rash and Associated Illness Center, a clinic that opened on August 6, 1997, in response to the need for a central facility for diagnosis of human illness acquired from Pfiesteria. Until the Pfiesteria toxin(s) is isolated and characterized, and laboratory diagnostic tests are available, physicians must be able to recognize Pfiesteria-human illness syndrome and intervene when symptoms, particularly memory loss and diarrhea, cause significant impairment in daily activities. There are no precedents for the treatment of Pfiesteria or any dinoflagellate toxin-related human illness reported in the literature. The successful use of cholestyramine reported here may provide a model for understanding dinoflagellate toxin physiology in the human body. This paper reports an uncontrolled observational study. When identification of the toxin is completed, a basis for properly controlled studies will be available.

Administration, Oral↗

PubMed1976

[Mathematical statistical evaluation of the trends of biological parameters during intermittent therapy].

Principle and method of the mathematico-statistical evaluation of an intermitting therapy are explained at the example of the cholestyramine treatment in incomplete obstruction of the bile ducts. The behavior of a biochemical parameter-e.g. the alkaline phosphatase activity and the cholesterol content of the serum-during this time is described with a total approximation function which is subdivided into several partial regression functions. The changes of the biochemical parameter during several periods with and without therapy, respectively, my be characterised and statistically judged from different points of view, e.g. as trend. Thus the clinical test of medicaments gains more objectivity, selectivity, dynamics and individuality. Thus in the example described the effect of cholestyramine (cuemid) decreasing the pathologically increased alkaline phosphatase activity and the increased cholesterol content of the serum and a return to the initial values and a slight deterioration, respectively, after discontinuation of the medicament with a probability of error up to alpha less than 0.001 on one patient could be proved.

Alkaline Phosphatase↗

PubMed1998

HMG-CoA reductase is not the site of the primary defect in phytosterolemia.

Phytosterolemia is an autosomal recessive disorder characterized by the excessive absorption, reduced excretion, and consequent high tissue and plasma levels of plant sterols, by the presence of tendon xanthomas, and by premature atherosclerosis. Low HMG-CoA reductase (HRase) activity and mass have been reported in liver and mononuclear leucocytes and low mRNA levels in liver from phytosterolemic subjects. These results led to the proposal that the primary defect in this condition involves the HRase gene locus. We examined this hypothesis in phytosterolemic subjects and heterozygous parents from four unrelated families. A variable number tandem repeat (VNTR) polymorphism of the HRase gene in the three informative families and a ScrFI restriction fragment length polymorphism (RFLP) within intron 2 of the gene in one of these families, segregated independently of the disease phenotype. Biological parentage was confirmed in the family in whom both polymorphisms failed to segregate with the disorder. These results conclusively exclude the HRase gene locus as the site of the primary defect in phytosterolemia. The study was extended by examining plasma levels of mevalonic acid and lathosterol, both markers of cholesterol biosynthesis, in response to cholestyramine, a bile acid sequestrant that is known to up-regulate HRase. Oral administration of cholestyramine resulted in a substantial (7.7-fold) increase in mevaIonic acid levels in two phytosterolemic subjects, compared with a 2.2-fold rise in their obligate heterozygote parents and a 2.3-fold increase in three healthy control subjects. The lathosterol/cholesterol (L/C) ratio showed a quantitatively similar response. Baseline levels of mevalonate and the L/C ratio were low in the phytosterolemic patients in conformity with reports of reduced cholesterol biosynthesis and HRase activity in this disorder. These functional data provide support for the concept that the primary defect in phytosterolemia does not affect a trans gene locus responsible for the constitutive expression or regulation of HMG-CoA reductase.

Adolescent↗

PubMed1988

Bile acid binding and hypocholesterolemic activity of a new anion exchange resin from 2-methylimidazol and epichlorohydrin.

A new anion exchange resin with an imidazolium salt on a epoxide polymer skeleton was synthesized. This white powder material was odorless and tasteless. The in vitro sodium cholate binding of this resin was much more potent than that of cholestyramine. The hypocholesterolemic activity of this resin in cholesterol-fed rabbits proved to be 4.3 times more potent than that of cholestyramine. These results suggest that effective reduction of plasma cholesterol may be achieved with lower doses of this resin.

Animals↗

PubMed1997

Metabolism of farnesol: phosphorylation of farnesol by rat liver microsomal and peroxisomal fractions.

In this study we provide evidence for the first time that rat liver microsomal and peroxisomal fractions are able to phosphorylate free farnesol to its diphosphate ester in a CTP dependent manner. The farnesyl diphosphate (FPP) kinase activity is decreased in whole liver homogenates obtained from rats treated with cholesterol and unchanged in homogenates obtained from rats treated with cholestyramine. In contrast, farnesyl pyrophosphatase (FPPase) activity, an enzyme which specifically hydrolyzes FPP to farnesol is only found in the microsomal fraction and is unaffected by treatment of rats with cholesterol or cholestyramine. In addition, we also demonstrate that farnesol can be oxidized to a prenyl aldehyde, presumably by an alcohol dehydrogenase (ADH), and that this activity resides in the mitochondrial and peroxisomal fractions.

Alcohol Dehydrogenase↗

PubMed1987

Absence of significant role of bile acids in diarrhea of a heterogeneous group of postcholecystectomy patients.

Twenty-five postcholecystectomy (PC) patients who underwent a diagnostic work-up for persistent diarrhea and six control subjects were studied. Fourteen of the 25 patients were also characterized by conditions other than PC which could play a role in the pathogenesis of the diarrhea. However, none of the patients had evidence of ileal disease or resection. The average follow-up of the patients after the study was approximately 4.4 years. Excretion, composition, and aqueous-phase concentrations of fecal bile acids were analyzed using gas-liquid chromatography. Eleven of the 25 PC patients showed an increased fecal bile acid excretion. In three of the 11 patients, the magnitude of the bile acid loss, which ranged from 2.26 to 3.34 mmol/24 hr, indicated the presence of severe bile acid malabsorption. The fecal bile acid composition showed a significant shift from secondary to primary bile acids. In spite of the presence of marked bile acid malabsorption, the aqueous-phase concentrations of the dihydroxy bile acids, chenodeoxycholic and deoxycholic acids, did not, with one exception, reach the secretory level of 1.5 mM. The relatively low aqueous concentrations were the result of low bile acid solubility, due to an acidic fecal pH. Only two of nine patients, one with severe, and the other with equivocal bile acid malabsorption, who were treated with cholestyramine, showed an improvement of the diarrhea. The findings of subsecretory bile acid concentrations in the fecal aqueous phase and of inconsistent therapeutic responses to cholestyramine indicate that, in spite of the presence of bile acid malabsorption, the diarrhea was, with few exceptions, not bile acid-induced. The results of the study also suggest that the diarrhea in many PC patients is multifactorial in origin.

Adult↗

PubMed1991

The Lipid Research Clinics Coronary Primary Prevention Trial: design, results, and implications.

The Coronary Primary Prevention Trial (CPPT) was the major clinical investigation conducted in the Lipid Research Clinics (LRC) Program. There were 12 North American clinics involved in this joint double-blind protocol. The hypothesis tested was: lowering plasma cholesterol in middle-aged men with primary hypercholesterolemia [plasma total cholesterol greater than or equal to 265 mg/dl (6.88 mm/l)] who are otherwise healthy leads to a reduction in coronary heart disease (CHD) as manifest by a reduction in definite myocardial infarction (fatal and nonfatal) over a 7-year follow-up of all participants. The trial was conducted in 3806 male volunteers between the ages of 35 and 59, who were randomly assigned to two equal groups. The treatment group received a moderate cholesterol-lowering diet plus cholestyramine: the placebo group received an identical diet plus a placebo. The study medication was administered at 24 g daily in divided doses. The participants were followed up bimonthly for an average of 7.4 years. The diet (daily cholesterol intake of about 400 mg and a polyunsaturated fat/saturated fat ratio of 0.8) lowered plasma cholesterol by an average of 4%, as designed. The cholestyramine group experienced average plasma total cholesterol (TC) lowering and plasma low-density lipoprotein cholesterol (LDC-C) lowering 8.5% and 12.6% greater than the placebo group, respectively. This resulted in a 19% reduction in definite myocardial infarction (P less than 0.05). The trial results for CHD deaths, nonfatal myocardial infarction,new positive exercise stress tests (P less than 0.001) new-onset angina (P less than 0.01) and coronary artery bypass surgery (P less than 0.06) and coronary artery bypass surgery ((p less than 0.06) were consistent with and supportive of the main findings of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗