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PubMed1989

The effects of mevinolin on the thiol/disulfide exchange between 3-hydroxy-3-methyglutaryl-coenzyme A reductase and glutathione.

The feeding of mevinolin plus cholestyramine to rats results in the production of a form of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR-CM) having thiol/disulfide redox properties different from those of 3-hydroxy-3-methylglutaryl-CoA reductase isolated from animals which had been given only cholestyramine (HMGR-C). The second-order rate constant for the inactivation of HMGR-CM by GSSG is 7-fold slower than for HMGR-C, while the second-order rate constant for the reactivation of oxidized enzyme by GSH is 100-fold slower. However, in the presence of saturating concentrations of both substrates, the rate constants for thiol/disulfide exchange are similar for both forms of the enzyme. HMGR-CM behaves as if a protein-glutathione mixed disulfide having a Kox of 27 +/- 4 is formed at equilibrium. In contrast, HMGR-C has previously been shown to form a protein-protein disulfide (Cappel, R. E., and Gilbert, H. F. (1988) J. Biol. Chem. 263, 12204-12212). Both forms of the enzyme are more difficult to oxidize thermodynamically in the presence of saturating levels of both substrates. For HMGR-CM, NADPH alone has no effect on the equilibrium constant for oxidation, but hydroxymethylglutaryl-CoA alone makes the enzyme approximately twice as difficult to oxidize. Under physiological conditions, HMGR-CM is thermodynamically more difficult to oxidize than HMGR-C. HMGR-C can be converted to HMGR-CM by in vitro treatment with mevinolinate. A direct or indirect interaction of mevinolin with HMGR-C results in some persistent, as yet undefined, structural alteration which inhibits the formation of a protein-SS-protein disulfide upon oxidation by glutathione disulfide.

Animals↗

PubMed1987

Bile loss in the acute intestinal radiation syndrome in rats.

The effects of bile duct ligation (BDL), choledochostomy, bile acid sequestering within the intestinal lumen by cholestyramine, and fluid and electrolyte replacement on survival time and development of diarrhea after whole-body exposure to doses of ionizing radiation that result in death from acute intestinal injury were studied. BDL significantly prolonged survival and delayed the onset of diarrhea after exposure to 137Cs gamma rays, fission neutrons, or cyclotron-produced neutrons in the range of doses that produce intestinal death or death from a combination of intestinal and hematopoietic injuries. Cannulation of the bile duct with exteriorized bile flow (choledochostomy) to protect the irradiated intestine from the mucolytic action of bile salts did not duplicate the effect of BDL in increasing survival time. Choledochostomy without fluid replacement eliminated the occurrence of diarrhea in 15.4 Gy irradiated rats. Diarrhea did occur in irradiated animals with choledochostomy if they received duodenal injections of fluid and electrolytes to replace the fluid lost as a result of bile drainage. Duodenal injection of fluid and electrolytes, however, had no significant effect on survival time in irradiated rats. In contrast, injection of fluid and electrolytes into the peritoneal cavity of irradiated rats resulted in an increase in survival time that was comparable to that observed after BDL. Addition of antibiotics to the peritoneally injected fluid and electrolytes further increased survival time (up to 9 days). This survival time approached that seen in animals receiving the same radiation dose but which had the intestine exteriorized and shielded to minimize radiation injury to the intestine. Postmortem histological examinations of the irradiated small intestine showed mucosal regeneration in these long-term survivors receiving fluid and antibiotic therapy. In contrast, duodenal injection of cholestyramine post irradiation to bind bile acids had no effect on survival time or diarrhea incidence. The conclusions from these experiments are that BDL prolongs survival and postpones the onset of diarrhea in irradiated rats dying from acute intestinal injury primarily by slowing down the loss of fluid and electrolytes and that bile acids play no significant role.

Animals↗

PubMed1987

On the possible use of the serum level of 7 alpha-hydroxycholesterol as a marker for increased activity of the cholesterol 7 alpha-hydroxylase in humans.

The possibility was investigated that the serum level of 7 alpha-hydroxycholesterol can be used as a marker for cholesterol 7 alpha-hydroxylase activity. Six patients with gallstone disease were found to have a mean level of 7 alpha-hydroxycholesterol in serum of 30 +/- 4 ng/ml (mean +/- SEM) as measured by isotope dilution-mass spectrometry, using deuterated 7 alpha-hydroxycholesterol as internal standard. After treatment with cholestyramine in a dose of 8 g twice daily for 2-3 weeks preoperatively, the serum level increased to 128 +/- 20 ng/ml (P less than 0.001). Eight other patients with gallstone disease had a mean level of 7 alpha-hydroxycholesterol in serum of 29 +/- 7 ng/ml. Treatment with chenodeoxycholic acid, 15 mg per kg body weight per day for 3-4 weeks before surgery, decreased the mean level to 20 +/- 7 ng/ml (P greater than 0.05). The activity of the cholesterol 7 alpha-hydroxylase in liver biopsies taken during operation was found to be 38 +/- 5 pmol/min per mg of protein in the group of patients treated with cholestyramine and 1.3 +/- 0.5 pmol/min per mg in the group of patients treated with chenodeoxycholic acid. Liver biopsies from a group of untreated patients (n = 13) had a mean cholesterol 7 alpha-hydroxylase activity of 7.6 +/- 1.5 pmol/min per mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Sorbent therapy of the porphyrias. V. Adsorption of the porphyrin precursors delta-aminolevulinic acid and porphobilinogen by sorbents in vitro.

The acute attacks of the acute hepatic porphyrias may be precipitated by the excessive intracellular accumulation of the porphyrin precursors delta-aminolevulinic acid (ALA) or porphobilinogen (PBG). Sorbents that bind porphyrin precursors in the gastrointestinal tract may interrupt their enterohepatic circulation, thus reducing the body burden of these materials and minimizing the frequency or severity of acute attacks. We have determined the adsorption capacities (Qm's) of several activated charcoals and the ion exchange resin cholestyramine for ALA and PBG. Qm's (mg ALA or PBG adsorbed/gm dry sorbent) were determined from Langmuir isotherms, which were derived from studies of the amount of porphyrin precursor adsorbed after the addition of a constant amount of ALA or PBG to varying amounts of sorbent. These experiments were carried out pH 8.2 in 0.1% desoxycholate, to simulate conditions of the small intestine. Extremely high Qm's were obtained for all charcoals and both porphyrin precursors; those for cholestyramine were one or several orders of magnitude lower. For ALA, the Qm of Gulf Bio-Systems Super Char charcoal (110 +/- 35 [SD]) was not significantly greater than that of Med-Corp Acta-Char charcoal (95 +/- 20), but it did exceed those of all other charcoals by a statistically significant amount. For PBG, the Qm of Super Char (68 +/- 14) was marginally greater than that of Mallinckrodt USP charcoal (42 +/- 21, t8 = 2.18, p approximately equal to 0.06), but it was significantly greater than that of Acta-Char charcoal (27 +/- 12). All sorbents adsorbed ALA or PBG at comparable rates, and the complex of sorbent and porphyrin precursor appeared to be undissociable.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗

PubMed1985

Transcriptional regulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver.

This study addresses whether transcriptional control of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver plays a role in determining the level of reductase mRNA. Isolated rat liver nuclei were allowed to elongate nascent RNA transcripts in the presence of [alpha-32P]CTP, and radiolabeled nuclear reductase RNA was quantitated by filter hybridization. Rats fed a diet supplemented with the drugs cholestyramine and mevinolin and having 20-60-fold induced levels of reductase mRNA exhibited levels of reductase transcription which were 20-fold higher than in rats fed an unsupplemented diet. Over 90% of the transcription of the reductase gene was inhibited by concentrations of alpha-amanitin which selectively inhibit RNA polymerase II. Administration of mevalonolactone (the end product of the reaction catalyzed by reductase) to rats fed cholestyramine and mevinolin caused an 80% decrease in the rate of reductase transcription by approximately 1 h. We conclude that under these conditions changes in reductase transcription are primarily responsible for the regulation of reductase mRNA levels.

Amanitins↗

PubMed1985

[Clinical significance of non-renal elimination mechanisms of methotrexate (MTX)].

Biliary MTX levels in one patient undergoing intermediate dose MTX therapy (500 mg/m2) were measured by HPLC. At the end of the 24 h infusion period they were found in the range of the corresponding serum levels. In one other patients undergoing high-dose MTX therapy (12 g/m2) MTX serum levels in the slow elimination phase were lowered by orally applicated cholestyramine. In one further patient who developed renal failure under high-dose MTX therapy total body clearance of MTX could be markedly improved by cholestyramine per os. The data presented, suggesting an appreciable biliary secretion of the drug in man, are discussed in view of the current concepts of enterohepatic circulation of MTX.

Abdominal Neoplasms↗

PubMed1985

Pruritus in hepatic cholestasis. Pathogenesis and therapy.

Pruritus associated with hepatic cholestasis may cause significant morbidity. Current evidence indicates that bile acids may not be the pruritogenic factor. Rather, the factor may be some other cholephilic anion or anions that bind to cholestyramine resin and are photolabile. Effective treatment modalities used currently include cholestyramine resin and phenobarbital. Phototherapy is a promising modality in which the mechanism and most effective wavelengths remain to be elucidated. Analysis of the possible role of non-steady state bile acid compartmentalization in the pathogenesis of pruritus is presented.

Adrenal Cortex Hormones↗

PubMed1985

Suitability of primary monolayer cultures of adult rat hepatocytes for studies of cholesterol and bile acid metabolism.

Monolayer cultures of hepatocytes isolated from cholestyramine-fed rats and incubated in serum-free medium converted exogenous [4-14C]cholesterol into bile acids at a 3-fold greater rate than did cultures of hepatocytes prepared from untreated rats. Cholic acid and beta-muricholic acid identified and quantitated by gas-liquid chromatography and thin-layer chromatography were synthesized by cultured cells for at least 96 h following plating. The calculated synthesis rate of total bile acids by hepatocytes prepared from cholestyramine-fed animals was approximately 0.058 micrograms/mg protein/h. beta-Muricholic acid was synthesized at approximately a 3-fold greater rate than cholic acid in these cultures. Cultured hepatocytes rapidly converted the following intermediates of the bile acid pathway; 7 alpha-hydroxy[7 beta-3H]cholesterol, 7 alpha-hydroxy-4-[6 beta-3H] cholesten-3-one, and 5 beta-[7 beta-3H]cholestane-3 alpha, 7 alpha, 12 alpha-triol into bile acids. [24-14C]Chenodeoxycholic acid and [3H]ursodeoxycholic acid were rapidly biotransformed to beta-muricholic acid. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity measured in microsomes of cultured hepatocytes decreased during the initial 48 h following plating, but remained relatively constant for the next 72 h. In contrast, cholesterol 7 alpha-hydroxylase activity appeared to decrease during the first 48 h, followed by an increase over the next 48 h. Despite the apparent changes in enzyme activity in vitro, the rate of bile acid synthesis by whole cells during this time period remained constant. It is concluded that primary monolayer cultures of rat hepatocytes can serve as a useful model for studying the interrelationship between cholesterol and bile acid metabolism.

Animals↗

PubMed1985

Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis.

We have measured plasma sterol composition in 14 subjects with sitosterolemia and xanthomatosis. In addition to elevated plasma phytosterol (campesterol 16 +/- 7 mg/dl and sitosterol 35 +/- 16 mg/dl) and normal to moderately high cholesterol levels (258 +/- 96 mg/dl), concentrations of 5 alpha-saturated stanols, cholestanol, 5 alpha-campestanol, and 5 alpha-sitostanol were at least 10 times greater than controls. Diets contained plentiful quantities of cholesterol and plant sterols, but only trace amounts of cholestanol (less than 2 mg/day) and no detectable 5 alpha-campestanol and 5 alpha-sitostanol, which indicated that the 5 alpha-saturated stanols were formed endogenously. Treatment with cholestyramine reduced plasma cholesterol and phytosterol levels by 45% and 5 alpha-saturated stanols by 55%. These results indicate that abnormally high plasma concentrations of cholestanol, 5 alpha-campestanol, and 5 alpha-sitostanol are found in subjects with sitosterolemia and xanthomatosis, and that treatment with cholestyramine effectively reduced elevated plasma sterol levels.

Adolescent↗

PubMed1985

[Lipoprotein lipase and lecithin-cholesterol-acyltransferase activity when lipoprotein metabolism is experimentally altered].

Lipoproteinlipase (LPL) and lecithin-cholesterol-acyltransferase (LCAT) activity was studied in rats in conditions of drug-induced (Clofibrat, cholestyramine, aethinyloestradiol) changes in lipid metabolism. Comparison of enzyme activity in three models of changed lipoprotein metabolism has revealed that the only model used (with aethinyloestradiol) leads to the uniform changes (decrease) in LPA and LCAT. Clofibrat increased LPL activity, with LCAT activity remaining unaffected. Cholestyramine caused no changes in LPL activity, but increased LCAT activity. The results obtained suggest that synergism in LPL and LCAT activity changes is registered only when lipolysis of triglyceride-saturated lipoproteins leads to the increase in the number of particles, similar in their structure and properties to high density lipoproteins, the basic LCAT structure.

Animals↗

PubMed1978

Cholesterol gallstones and biliary lipid metabolism in the primate.

A primate model for the study of cholesterol gallstones is described. Bile became supersaturated with cholesterol in 7 female adult baboons with exteriorized enterohepatic circulations during 0.2 g per kg per day of cholestyramine treatment. Cholestyramine decreased bile acid pool size (1.38 +/- 0.7 to 0.45 +/- 0.02 mmole, P less than 0.001) and secretion rate (12.7 +/- 0.9 to 5.6 +/- 0.5 mmoles per 24 hr) while cholesterol secretion remained unaltered. Although biliary lipid and bile acid composition were similarly affected by treatment in both cholecystectomized and intact animals, cholesterol stones formed only in the latter. Thus metabolic alterations in biliary lipid metabolism as well as the presence of the gallbladder were necessary for stone formation.

Animals↗

PubMed1966

Bile acids in the rat: studies in experimental occlusion of the bile duct.

Bile acids in the plasma, urine, and small intestine of adult male rats with occluded bile ducts have been studied using a method of high specificity for their determination. After bile duct ligation cholic acid rapidly accumulates in the plasma for 8 hr, remains high for a further 8 hr, and subsequently diminishes; bile acids disappear from the small intestine. During the first 12 hr after bile duct ligation the excretion of trihydroxy acids in the urine was 10 times that of the dihydroxy acids. Subsequently the two excretion rates became equal. Because bile acids have been implicated in the etiology of hepatic damage following bile duct ligation, studies have been made of the effect on the liver of removing (with cholestyramine) and supplementing (with cholic acid) the intestinal bile acid pool. The addition of cholestyramine to the stock diet prevented the rise in trihydroxy bile acids after bile duct ligation, but did not prevent the development of histological abnormalities in the liver. Supplementing the diet with cholic acid raised the plasma cholic acid levels but had little effect on the hepatic histological findings.

Animals↗

PubMed1984

New approaches for treatment of humans exposed to a slowly excreted environmental chemical (chlordecone).

Workers in a small factory that manufactured the organochlorine pesticide chlordecone were exposed to large amounts of this toxic material for many months. Toxic manifestations prominently involved the nervous system, liver and testes. Chlordecone was present in high concentrations in samples of blood, liver, and fat from these workers. A plasmaphoresis experiment indicated that chlordecone is rapidly transferred from tissues to blood. However, hemoperfusion was unsuccessful for removing chlordecone from the body because chlordecone is avidly bound by plasma proteins. Based on the observation that stool contains only a small fraction of the substantial amounts of chlordecone excreted in bile, we administered orally cholestyramine, a nonabsorbable resin that binds chlordecone in vitro. Cholestyramine increased fecal excretion of chlordecone and accelerated the rate of disappearance of the pesticide from the body. This was accompanied by amelioration of the clinical manifestations of toxicity, indicating that the subacute toxic effects of chlordecone are reversible. We conclude that therapy with binding agents taken orally provide a safe and effective means for treatment of humans poisoned with chlordecone and, possibly with other organochlorine pesticides.

Adipose Tissue↗

PubMed1984

Hypertrophy of the rat Golgi complex during enhancement of cholesterol and bile acids synthesis.

There are some evidences that the Golgi apparatus could be involved in bile salts transport. In this study we investigate the morphology of the Golgi apparatus in rats with a chronic bile fistula or treated with 4% cholestyramine, a bile salts chelating agent. In both models liver histology was normal by light microscopy. With electron microscopy--compared to sham groups--the only obvious change was the enlargement of the Golgi complex. Morphometric data confirmed that the Golgi rich area volume density was almost doubled after chronic bile fistula or cholestyramine treatment. These data give another support for the participation of the Golgi complex in bile salts transport.

Animals↗

PubMed1984

Diurnal rhythm of rat liver mRNAs encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase. Correlation of functional and total mRNA levels with enzyme activity and protein.

Rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase exhibits a diurnal rhythm of activity which coincides with a diurnal rhythm of reductase protein and reductase mRNA levels. This diurnal rhythm of reductase activity, polypeptide mass, and mRNA exists in rats fed a normal diet (unsupplemented rat chow) and in rats fed a diet supplemented with cholestyramine plus or minus mevinolin. Levels of reductase protein were determined by 8 M urea/sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Reductase mRNA was measured by in vitro translation or blot hybridization of liver RNA. Functional reductase mRNA levels in rats fed a normal diet were approximately 10-fold higher during the middle of the dark cycle than during the middle of the light cycle. Maximum induction of functional reductase mRNA was observed in rats fed cholestyramine and mevinolin. This latter level was 157-fold higher than the level measured at the diurnal low point in rats fed a normal diet. Blot hybridization of liver RNA showed two predominant mRNAs of 4.6 and 4.2 kilobase pairs and a minor species at 6.9 kilobase pairs. These mRNAs exhibited a diurnal rhythm for rats on all three diets and reached peak levels during the 12-h dark period. These data indicate that the diurnal rhythm of reductase mass and activity is closely paralleled by the level of its mRNA.

Animals↗

PubMed1982

On the enterohepatic circulation of bile acids in man.

1. Fasting concentrations of C, CD and D were determined in systemic and portal venous serum in gallstone patients and controls (patients with adenomyoma of the gallbladder) undergoing cholecystectomy. No differences were observed between the two groups either in systemic or portal serum concentrations of the bile acids or in their hepatic uptake. Ketonic bile acid concentrations amounted to 9% and 8% of the non-oxidized bile acids in the systemic and portal circulation, respectively. 2. Fasting systemic and portal venous serum concentrations of bile acids were measured in gallstone patients fed with C and CD prior to cholecystectomy. Treatment with CD increased the total portal inflow of bile acids by 60%, whereas C treatment did not alter this total inflow compared with controls. This difference may partly explain why hepatic bile is unsaturated during treatment with CD, but not with C. 3. The postprandial concentrations of bile acids were determined in the systemic and portal venous circulation in cholecystectomized patients. The systemic venous bile acid level reflected the portal venous level. The estimated hepatic uptake of the individual bile acids was highly efficient and could not be saturated during maximal physiological portal inflow to the liver. The existence of a lymphatic transport of bile acids, calculated to correspond to about 0.2% of the portal transport, was demonstrated in four patients undergoing renal transplantation. 4. Cholestyramine treatment was shown to reduce the plasma cholesterol level in patients with familial hypercholesterolaemia without lowering the fasting systemic level of total bile acids. Nor did this treatment reduce the fasting portal inflow of total bile acids. The total bile acid concentration in healthy volunteers during treatment showed a 40% reduction postprandially, but not in the fasting state, indicating that the effect of cholestyramine on hepatic cholesterol metabolism is the consequence of a reduced postprandial inflow of portal bile acids. The effects of the loss of the active site of bile acid absorption on the postprandial serum bile acid pattern were studied in patients with ileal resections. In general, the postprandial response of C was reduced whereas that of CD remained less affected.

Bile Acids and Salts↗

PubMed1982

Drug-nutrient interaction.

The effect of certain drugs on nutrient metabolism is discussed. Antituberculotic drugs such as INH and cycloserine interfere with vitamin B6 metabolism and may produce a secondary niacin deficiency. Oral contraceptives interfere with the metabolism of folic acid and ascorbic acid, and in cases of deficient nutrition, they also seem to interfere with riboflavin. Anticonvulsants can act as folate antagonists and precipitate folic acid deficiency. Therefore, in some cases, supplementation with folate has been recommended simultaneously with anticonvulsant therapy. Cholestyramine therapy has been associated with malabsorption of vitamins; several reports suggest that cholestyramine affects absorption of the fat-soluble vitamins K and D and, in addition, may alter water-soluble vitamins, including folic acid. The study of the interaction of drugs and nutrients is an area that deserves a greater attention in the future, especially in groups where nutrient deficiencies may be prevalent.

Anticonvulsants↗

PubMed1982

Normal hepatic vitamin-D metabolism in icteric primary biliary cirrhosis associated with pronounced vitamin-D deficiency symptoms.

The intestinal absorption and hepatic metabolism of vitamin D were studied in a woman with icteric primary biliary cirrhosis (PBC) complicated by pronounced bone pain and muscle weakness due to vitamin-D deficiency. The patient had a markedly reduced intestinal absorption of vitamin D, while the 25-hydroxylation of this vitamin was found to be normal despite the presence of longstanding icterus. The malabsorption of fat-soluble compounds secondary to the cholestasis was probably further impaired by several years of cholestyramine treatment. Administration of 1.25-(OH)2D3 increased intestinal calcium absorption, normalized serum calcium and increased bone mineral content of the proximal tibia. Furthermore, drastic improvement of muscle weakness and relief of bone pain were observed. It is recommended that repeated measurements of serum 25-(OH)D should be carried out in patients with PBC, and especially in those treated with cholestyramine. In certain vitamin D deficient patients, studies using radio-labelled vitamin D may provide clinically valuable information as to the exact site of the underlying disturbances.

Cholestyramine Resin↗