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PubMed2005

Recent advances on the use of adsorbent materials for detoxification of Fusarium mycotoxins.

The extensive use of adsorbents in the livestock industry has led to the introduction of a wide range of new products on the market, most of them claiming high in vitro mycotoxin adsorption capacity. However, adsorbents that may appear effective in vitro do not necessarily retain their efficacy when tested in vivo. Studies performed in our laboratory during the past few years aiming to evaluate the efficacy of various adsorbent materials in binding Fusarium mycotoxins are reported. Adsorption experiments were performed in in vitro screening tests for Fusarium mycotoxins at different pHs; by in vivo tests using the increase of the sphinganine to sphingosine ratio in rat urine and tissues as a biomarker of fumonisin exposure; and by a dynamic, computer-controlled, gastrointestinal model simulating the gastrointestinal tract of healthy pigs. Most of the commercially available mycotoxin-binders failed in sequestering in vitro Fusarium mycotoxins. Only for a small number of adsorbent materials was the ability to bind more than one mycotoxin demonstrated. Cholestyramine was proven to be an effective binder for fumonisins and zearalenone in vitro, which was confirmed for zearalenone in experiments using a dynamic gastrointestinal model and for fumonisins in in vivo experiments. No adsorbent materials, with the exception of activated carbon, showed relevant ability in binding deoxynivalenol and nivalenol. The in vitro efficacy of activated carbon toward fumonisins was not confirmed in vivo by the biomarker assay. The dynamic gastrointestinal model was a reliable tool to study the effectiveness of adsorbent materials in reducing the bioaccessibility of Fusarium mycotoxins, as an alternative to the more difficult and time-consuming studies with domestic livestock.

Adsorption↗

PubMedDate not supplied

Therapeutic approaches for chlordecone poisoning in humans.

Due to lack of adequate industrial safety measures, workers in a small factory that manufactured the organochlorine pesticide chlordecone were exposed to large amounts of this toxic material for many months. High concentrations of chlordecone were present in samples of blood, liver, and fat from these workers. Toxic manifestations prominently involved the nervous system, liver and testes. Although a plasmaphoresis experiment indicated that chlordecone is rapidly transferred from tissues to blood, attempts to employ hemoperfusion as a means for removing chlordecone from the body were unsuccessful because chlordecone is avidly bound by plasma proteins and was not extracted by the hemoperfusion sorbents. An alternative approach to therapy was based on the observations that stool contains only a small fraction of the substantial amounts of chlordecone excreted in bile. Oral administration of cholestyramine, a nonabsorbable resin that binds chlordecone in vitro, increased fecal excretion of chlordecone and accelerated its disappearance from the body. This treatment was accompanied by amelioration of the clinical manifestations of toxicity, indicating that the subacute toxic effects of chlordecone are reversible. Studies of chlordecone excretion in one patient with a surgically created bile fistula disclosed the existence of the novel, nonbiliary mechanism for excretion of chlordecone in the stool. Further physiological studies are needed to explore the possible role of the gut in the excretion of many kinds of slowly eliminated lipophilic toxins.

Bile↗

PubMed1977

Hyperoxaluria and calcium oxalate nephrolithiasis after jejunoileal bypass.

Patients with ileal disease, ileal resection, and jejunoileal bypass are at increased risk of forming calcium oxalate renal calculi because of enhanced absorption of dietary oxalate. Intraluminal solubility of oxalate is an important determinant for hyperabsorption and may be regulated by intraluminal concentration of calcium and fatty acids. Malabsorbed bile salts and fatty acids may alter intestinal permeability, leading to increased passive diffusion of oxalate. Management includes a diet low in oxalate and fat content, dietary calcium of 750 mg/day, and cholestyramine.

Bile Acids and Salts↗

PubMed1980

Dietary fiber and blood lipids: treatment of hypercholesterolemia with guar crispbread.

Eleven hyperlipidemic patients took an average of 13 g guar in crispbread form over 2- to 8-week periods. Eight weeks' treatment (seven patients) reduced total serum cholesterol by 13% (P less than 0.002) while high-density lipoprotein cholesterol was unchanged. A 13% nonsignificant reduction was also seen in serum triglyceride. Comparison of blood lipid changes over 2-week periods showed guar crispbread to be as effective as guar given in hydrated (eight patients) or semihydrated form (four patients). In addition total serum cholesterol was lowered significantly (11%, P less than 0.05) in five patients where cholestyramine was ineffective. Due to its acceptability, guar crispbread is likely to prove a useful cholesterol-lowering agent.

Adult↗

PubMed1980

A novel use of chitosan as a hypocholesterolemic agent in rats.

A series of experiments with male rats clearly demonstrated the hypocholesterolemic activity of dietary chitosan. On feeding a high cholesterol diet for 20 days, addition of 2 to 5% chitosan resulted in a significant reduction, by 25 to 30%, of plasma cholesterol without influencing food intake and growth. The concentration of liver cholesterol and triglyceride also decreased significantly. Plasma, but not liver cholesterol-lowering effect, was roughly comparable with that of cholestyramine. Chitosan at the 10% level further reduced plasma cholesterol, but depressed growth. Also, finer chitosan particles tended to restrain growth even at the 2% level. In rats fed a cholesterol-free diet containing 0.5% chitosan for 81 days, the concentration of serum cholesterol was the same with that of the corresponding control, but relatively more cholesterol existed as high-density lipiproteins and less as very low-density lipoproteins. Dietary chitosan increased fecal excretion of cholesterol, both exogenous and endogenous, while that of bile acids remained unchanged. There was no constipation or diarrhea. A proper supplementation of chitosan to the diet seemed to be effective in lowering plasma cholesterol.

Animals↗

PubMed1995

Lack of efficacy of low-dose sitostanol therapy as an adjunct to a cholesterol-lowering diet in men with moderate hypercholesterolemia.

Plant sterols have been shown to reduce dietary cholesterol absorption and hence, total and low-density-lipoprotein (LDL)-cholesterol concentrations in humans. In this study the cholesterol-lowering effects of dietary supplementation with the hydrogenated plant sterol sitostanol (3 g/d) were tested in 33 men with moderate hypercholesterolemia who were consuming an outpatient diet in which dietary cholesterol was restricted to < 200 mg/d. Sitostanol therapy did not significantly lower LDL cholesterol compared with the diet alone. Similarly, sitostanol therapy in conjunction with a cholesterol-lowering regimen of diet and 8 g cholestyramine did not significantly lower LDL-cholesterol concentrations. Hence, although previous reports have suggested that low-dose sitostanol therapy is an effective means of reducing LDL-cholesterol concentrations, its effectiveness may be attenuated when the diet is low in cholesterol.

Adult↗

PubMed1993

Pharmacokinetics of fluvastatin and specific drug interactions.

Fluvastatin sodium (Lescol) is the first synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor to be studied extensively in humans. Absorption of fluvastatin is complete and unaffected by the presence of food. Systemic exposure is limited because of extensive sequestration by the liver and/or first-pass metabolism, a plasma half-life of approximately 30 min, no circulating active metabolites, and no accumulation of drug during chronic dosing. Approximately 95% of a single dose of fluvastatin is excreted via the biliary route with less than 2% as the parent compound. Studies investigating the effect of food on fluvastatin pharmacokinetics have demonstrated marked reductions in the rate of bioavailability (Cmax) of 40% to 60%. A comparison of drug administration with the evening meal or at bedtime revealed no significant differences in either the extent of bioavailability (area under the curve; AUC) or pharmacodynamic effect [reduction in low-density lipoprotein cholesterol (LDL-C)]. Relative to the general population, plasma fluvastatin concentrations do not vary as a function of either age or gender. Administration of a single 40-mg dose to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both AUC and Cmax. Drug interaction studies with fluvastatin and cholestyramine (CME) demonstrated a lower rate and extent of fluvastatin bioavailability; no impact on efficacy was demonstrated when CME was given 4 h before fluvastatin dosing in clinical trials. Interaction studies with niacin and propranolol demonstrated no effects on fluvastatin plasma levels, and fluvastatin administered to a patient population chronically receiving digoxin had no effect on the AUC of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1981

The effects of cholic acid and bile salt binding agents on 1,2-dimethylhydrazine-induced colon carcinogenesis in the rat.

The theory that bile salts may be colon tumour promoters was tested in the dimethylhydrazine (DMH)-induced rat colon cancer model. Fifty Wistar rats were randomly allocated to one of five experimental group (n = 10), all fed the same standard diet. One group served as saline-injected controls, while the other four groups received DMH (20 mg/kg body weight/rat/week s.c.) for 20 weeks. In addition, each of the DMH-injected groups concurrently received 20 weekly i.g. instillations of one of the following: cholic acid (a bile acid); cholestyramine or aluminium hydroxide (both bile acid binding agents), or water. After a years observation period, all the controls were alive and tumour-free, while all the DMH-injected rats had died of histologically proven colon cancer. Irrespective of the type of gastric instillate, there were no significant differences between the groups in terms of time to tumour presentation, survival, in the necropsy incidence of primary or metastatic colon cancer, or in the numbers of colon tumours per group. The data suggest that bile salts and bile salt binding agents are not colon tumour promoters in the rat. The bile salt theory of colon carcinogenesis may need reappraisal.

1,2-Dimethylhydrazine↗

PubMedDate not supplied

Effect of bismuth subsalicylate on chronic diarrhea in childhood: a preliminary report.

Stools collected from 39 infants and children with chronic nonspecific diarrhea and from 10 age-matched controls were examined for bile acid content with use of gas-liquid chromatography. Values were correlated with stool color. Mean concentration of bile acids in green stools (7.7 +/- 1.52 mg/g dry weight) was significantly higher than that in brown stools (3.76 +/- 0.7 mg/g dry weight) and in control stools (1.42 +/- 0.35 mg/g dry weight). In patients with green diarrhea, treatments with cholestyramine and bismuth subsalicylate (Pepto-Bismol) were equally effective in decreasing stool frequency, with the latter being more effective in decreasing water content. Patients with brown stools had an insignificant response to therapy.

Bile Acids and Salts↗

PubMed1998

Dietary psyllium increases fecal bile acid excretion, total steroid excretion and bile acid biosynthesis in rats.

Psyllium, a source of dietary fiber rich in soluble components results in lower serum cholesterol concentration in several species. Suggested mechanisms for the hypocholesterolemic effect include a greater excretion of fecal bile acids and total steroids, and up-regulation of bile acid biosynthesis. The activity of cholesterol 7alpha-hydroxylase (7alphaOHase), the rate limiting enzyme in bile acid biosynthesis, is higher in rats fed 5% psyllium. Whether this higher activity corresponds to an increase in mRNA levels has not been determined. Four groups of 10 rats were fed a semipurified diet containing 5% cellulose (CEL; control), 5% cellulose plus 1% cholic acid (CCA), 5% cellulose plus 2% cholestyramine (CHY) or 5% psyllium hydrocolloid (PSY) for 3 wk. Liver cholesterol concentration, fecal bile acid and total steroid excretion, 7alphaOHase activity and 7alphaOHase mRNA levels were measured. Liver cholesterol content in rats fed CCA was significantly higher than in all other groups. Rats fed CHY and PSY had significantly lower liver cholesterol content than those fed CEL. Total fecal steroid and bile acid excretions were significantly greater in rats fed CCA, CHY and PSY than in those fed CEL. Activities and mRNA levels of 7alphaOHase in rats fed CHY and PSY were significantly higher than in rats fed CEL or CCA. These data indicate that feeding psyllium to rats increases fecal bile acid and total steroid excretion as well as 7alphaOHase activity and 7alphaOHase mRNA levels.

Animals↗

PubMed1999

Increased fecal bile acid excretion and changes in the circulating bile acid pool are involved in the hypocholesterolemic and gallstone-preventive actions of psyllium in hamsters.

The lipid-lowering effect of psyllium (PSY) is well established. Enhanced fecal bile acid excretion and a stimulation of hepatic bile acid synthesis are discussed as primary mechanisms of this action. To further examine the effect of bile acid excretion and specifically of compositional alterations in the bile acid pool on the cholesterol-lowering and gallstone-preventing action of PSY, male golden Syrian hamsters were fed lithogenic diets containing 5 g/100 g fat, 0.4 g/100 g cholesterol and 0 (control), 4 or 6% PSY or 1% cholestyramine (CHY). PSY significantly lowered plasma total cholesterol and triacylglycerol at a magnitude comparable to that induced by CHY. Although hepatic cholesteryl ester accumulation was completely inhibited by CHY, PSY did not prevent the hepatic storage of esterified cholesterol. PSY and CHY caused distinct alterations in the bile acid profile. PSY caused a selective reduction of taurine-conjugated bile acids, especially of taurochenodeoxycholate. As a result, the glycine:taurine conjugation and the cholate:chenodeoxycholate ratios were significantly higher in PSY-fed hamsters. PSY and CHY normalized the lithogenic index and prevented cholesterol gallstone formation compared with controls. Daily fecal bile acid excretion was approximately 400% greater in hamsters fed 6% PSY, whereas CHY caused an 11-fold increase. Daily neutral sterol excretion did not differ in PSY-fed hamsters but was >100% greater in those fed CHY than in controls. These data emphasize the potent lipid-lowering effect of PSY. Increased fecal bile acid excretion and alterations of the circulating bile acid pool by removal of dihydroxy bile acids (e.g., taurochenodeoxycholate) appear to be main modulators of the hypocholesterolemic action of PSY by leading to an up-regulation of hepatic bile acid synthesis.

Analysis of Variance↗

PubMed1997

Purification and characterization of two mevalonate pyrophosphate decarboxylases from rat liver: a novel molecular species of 37 kDa.

The biosynthesis of cholesterol is regulated mainly by HMG-CoA reductase, however, recent studies indicated the pivotal role of another enzyme in cholesterol homeostasis. A previous report showed a marked decrease in the activity of mevalonate pyrophosphate decarboxylase (MPD) in stroke-prone spontaneously hypertensive rats and its possible involvement in the pathogenesis of the disorder. In this study, we purified liver MPD from rats fed a diet containing cholestyramine and pravastatin (CP diet) using conventional chromatographic techniques. We obtained two electrophoretically homogeneous enzyme preparations; 45 and 37 kDa proteins with specific activities of 8.0 and 7.4 micromol/min/mg, respectively. The enzymes showed similar molecular weights of 90 kDa, as judged on gel permeation chromatography. A kinetic study indicated apparent Km values for mevalonate pyrophosphate and ATP of 22.7 microM and 0.71 mM, respectively, for the 45 kDa MPD, and 20.0 microM and 0.80 mM, respectively, for the 37 kDa MPD. Half maximum activities were observed at 1.5 mM and 1.1 mM Mg2+ for the 45 and 37 kDa MPDs, respectively. Both enzymes required ATP as a phosphate acceptor, and in addition Mg2+, Mn2+, and Co2+ were effective as divalent cations. The optimum pH for both enzymes was 7.0. The isoelectric points for the 45 and 37 kDa MPDs were 5.6 and 5.4, respectively. Polyclonal antiserum raised against the 45 kDa enzyme detected both the 45 and 37 kDa bands on immunoblots with CP diet-induced liver crude extract as an antigen. However, non-induced liver contained the 45 kDa protein but not the 37 kDa protein. These results indicated that the CP diet induced a new species, 37 kDa, of MPD which is characteristically and immunologically very similar to the well-known 45 kDa MPD.

Animals↗

PubMed1999

Structure, evolution, and liver-specific expression of sterol 12alpha-hydroxylase P450 (CYP8B).

The rat CYP8B cDNA encoding sterol 12alpha-hydroxylase was cloned and sequenced. The amino acid sequence of the heme-binding region of CYP8B was close to those of CYP7A (cholesterol 7alpha-hydroxylase) and CYP7B (oxysterol 7alpha-hydroxylase). Molecular phylogenetic analysis suggests that CYP8B and the CYP7 family derive from a common ancestor. The P450s of the CYP7 and CYP8 families, except for CYP8A (prostacyclin synthase), catalyze the oxygenation of sterols from an alpha surface in the middle of the steroid skeleton. These facts suggest that CYP8B is a P450 closely linked to those of the CYP7 family. CYP8B was expressed specifically in liver. Hepatic CYP8B mRNA level and the 12alpha-hydroxylase activity were altered by cholestyramine feeding, starvation, streptozotocin-induced diabetes mellitus, and administration of clofibrate, dexamethasone or thyroxin, indicating the pretranslational regulation of CYP8B expression. The enhanced CYP8B mRNA expression in streptozotocin-induced diabetic rats was significantly decreased by insulin within 3 h of its administration. These facts demonstrate a regulatory role of insulin in CYP8B expression as a suppressor.

Amino Acid Sequence↗

PubMed2001

Growth hormone reduces plasma cholesterol in LDL receptor-deficient mice.

Growth hormone (GH) has pleiotropic effects on cholesterol and lipoprotein metabolism. Pituitary GH is important for the normal regulation of hepatic LDL receptors (LDLR), for the enzymatic activity of bile acid regulatory cholesterol 7alpha-hydroxylase (C7alphaOH), and for the maintenance of resistance to dietary cholesterol. The present study aimed to determine whether GH has beneficial effects on plasma lipids and hepatic cholesterol metabolism in mice devoid of LDLR. Compared with wild-type controls, LDLR-deficient mice had approximately 250% elevated plasma total cholesterol and approximately 50% increased hepatic cholesterol levels; hepatic HMG CoA reductase activity was reduced by 70%, whereas C7alphaOH activity was increased by 40%. In LDLR mice, GH infusion reduced plasma cholesterol and triglycerides up to 40%, whereas HMG CoA reductase and C7alphaOH activities were stimulated by approximately 50% and 110% respectively. GH also stimulated HMG CoA reductase and C7alphaOH activities in control mice, whereas hepatic LDLR and plasma lipoproteins were unchanged. The effects of cholestyramine and atorvastatin on C7alphaOH in LDLR-deficient mice were potentiated by GH, and this was associated with a further reduction in plasma cholesterol. GH treatment reduces plasma cholesterol and triglycerides and stimulates C7alphaOH activity in mice devoid of LDLR, particularly in combination with resin or statin treatment. The potential of GH therapy in patients with homozygous familial hypercholesterolemia should be evaluated.

Animals↗

PubMed1976

Identification of the jaundiced infant who is likely to recover without surgical intervention.

A series of 32 infants with persistant jaundice in whom an unequivocal differentiation between intrahepatic cholestasis and biliary atresia could not be made is reviewed. A protocol including Lipoprotein-X (LP-X) determinations before and after a short course of cholestyramine (CSM) was carried out in all. A fall in serum LP-X after CSM indicates the presence of patent extrahepatic bile ducts (even microscopic) which will function without benefit of hepatic portoenterostomy. A rise in LP-X levels after CSM means an atretic biliary system. The LP-X, CSM protocol was not able to differentiate between the anatomical variants of biliary atresia that may respond to hepatic portoenterostomy and those that will not. Patent bile ducts (even microscopic) in the porta hepatis and/or proximal hepatoduodenal ligament, which are in continuity with intrahepatic ducts, must be present if hepatic portoenterostomy is to be successful. None of our 12 infants undergoing hepatic portoenterostomy showed evidence of bile excretion after the procedure. Microscopic study of serial sections taken through the excised hepatoduodenal ligament tissues of these 12 infants revealed that none had anatomical findings conducive to the success of the operation.

Bile Ducts↗

PubMed1977

Sclerosing cholangitis and primary biliary cirrhosis--a disease spectrum?

Sclerosing diseases of the biliary system encompass a spectrum ranging from primary sclerosing cholangitis (usually of the extrahepatic biliary tree) to primary biliary cirrhosis of the intrahepatic bile canaliculi. In a study of 35 patients with primary intra- and extrahepatic biliary sclerosis, age of onset, sex distribution, symptomatology, associated diseases, radiographic abnormalities and chemical profile were considered. The difficulty of differentiating sclerosing cholangitis and biliary cirrhosis from other causes of obstructive jaundice preoperatively was stressed, in addition to points of differential clinical and laboratory findings. The etiology of these entities as well as the possibility that they represent variant clinical manifestations of the same disease process were also considered. Mechanical and pharmacological treatment alternatives that were attempted included drainage procedures, the easiest and most widely used of which was the T-tube. However, this could prove to be a source of infection and should therefore be removed early, inasmuch as cholangitis represents a major cause of morbidity. Steroids have been used with varying effectiveness; subjective improvement was generally attained, although objective improvement has been difficult to document. When choleuretics and cholestyramine were administered, we noted significant palliation. Antibiotics were reserved for treatment of cholangitis. Until the underlying etiology of this rare malignant sclerosing process is found, only symptomatic treatment can be offered.

Adult↗

PubMed1993

Postcholecystectomy diarrhea from villous atrophy of the terminal ileum.

We report a 60-year-old man with intermittent diarrhea for 15 years which was worsened by cholecystectomy. The results of routine laboratory tests, x-ray studies of the gut, and endoscopy were normal. Fecal fat excretion was normal, but total bile acid excretion was increased in the alkaline feces. The retention of 75SeHCAT was low. Jejunal mucosal biopsy showed normal mucosa. Ileal biopsy was performed at ileoscopy some 10 to 15 cm proximal to the ileocecal valve. Scanning-electron and light microscopy showed a transitional zone between villous atrophy in the distal and normal mucosa in the proximal part of the biopsy specimen. The response of diarrhea to cholestyramine treatment was unequivocal, suggesting bile acid malabsorption. The increased enterohepatic cycling of bile acids after cholecystectomy may be responsible for a decrease in their ileal uptake. Very often, as in our patient, the diarrhea precedes cholecystectomy and is considerably increased by it. Cholecystectomy may unmask a previously unrecognized bile acid transport defect. In our patient, this defect might have been caused by the villous atrophy of the terminal ileum.

Bile Acids and Salts↗

PubMed1984

Familial intrahepatic cholestasis associated with progressive neuromuscular disease and vitamin E deficiency.

Three Japanese patients with familial progressive intrahepatic cholestasis developed complications involving neurologic abnormalities characterized by ataxia and pigmentary retinopathy. Serum vitamin E concentrations were extremely low in all patients, suggesting a long-term vitamin E deficiency. High dose oral supplementation of alpha-tocopherol produced normal serum vitamin E levels in two patients. Parenteral administration of vitamin E resulted in no clinical improvement in one patient who first received the treatment at 14 years of age. In the other two patients, the progression of neurological abnormalities was slowed by vitamin E supplementation. Cholestyramine treatment resulted in an apparent decrease in serum vitamin E levels despite oral alpha-tocopherol supplementation.

Adolescent↗