Preclinical Development of U3-1784, a Novel FGFR4 Antibody Against Cancer, and Avoidance of Its On-target Toxicity.

The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.

Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.

Steam cooking significantly improves in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage.

Bile acid binding capacity has been related to the cholesterol-lowering potential of foods and food fractions. Lowered recirculation of bile acids results in utilization of cholesterol to synthesize bile acid and reduced fat absorption. Secondary bile acids have been associated with increased risk of cancer. Bile acid binding potential has been related to lowering the risk of heart disease and that of cancer. Previously, we have reported bile acid binding by several uncooked vegetables. However, most vegetables are consumed after cooking. How cooking would influence in vitro bile acid binding of various vegetables was investigated using a mixture of bile acids secreted in human bile under physiological conditions. Eight replicate incubations were conducted for each treatment simulating gastric and intestinal digestion, which included a substrate only, a bile acid mixture only, and 6 with substrate and bile acid mixture. Cholestyramine (a cholesterol-lowering, bile acid binding drug) was the positive control treatment and cellulose was the negative control. Relative to cholestyramine, in vitro bile acid binding on dry matter basis was for the collard greens, kale, and mustard greens, 13%; broccoli, 10%; Brussels sprouts and spinach, 8%; green bell pepper, 7%; and cabbage, 5%. These results point to the significantly different (P < or = .05) health-promoting potential of collard greens = kale = mustard greens > broccoli > Brussels sprouts = spinach = green bell pepper > cabbage as indicated by their bile acid binding on dry matter basis. Steam cooking significantly improved the in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage compared with previously observed bile acid binding values for these vegetables raw (uncooked). Inclusion of steam-cooked collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage in our daily diet as health-promoting vegetables should be emphasized. These green/leafy vegetables, when consumed regularly after steam cooking, would lower the risk of cardiovascular disease and cancer, advance human nutrition research, and improve public health.

Lipid-lowering effects of methanolic extract of Vernonia amygdalina leaves in rats fed on high cholesterol diet.

We investigated the lipid-lowering effects of methanolic extract of Vernonia amygdalina (VA) leaves in rats fed an high cholesterol diet, and compared with a standard hypolipidemic drug, Questran (Qu). The effects of VA on the lipid profile were assessed by measuring the levels of total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, lipid peroxidation (LPO), phospholipid, and glutathione (GSH) in the plasma and liver of the rats. Administration of cholesterol at a dose of 30 mg/0.3 ml, five times in a week for nine consecutive weeks resulted in a significant increase (p < 0.05) in plasma and post mitochondrial fraction (PMF) cholesterol levels by 33% and 55%, respectively. However, treatment with extract of VA at doses of 100 and 200 mg/kg caused a dose dependent reduction in the plasma and PMF cholesterol by 20%, 23% and 23%, 29%, respectively. Similar reduction in cholesterol levels was obtained in Qu-treated rats. Furthermore, VA at 200 mg/kg decreased the plasma and PMF LDL-cholesterol levels by 23% and 49%, and also decreased plasma and PMF triglyceride levels by 29% and 28%, respectively. Also, VA at 100 and 200 mg/kg caused a dose-dependent increase in plasma HDL-cholesterol levels by 41% and 59%, respectively. However, there were no significant differences (p > 0.05) in the PMF HDL-cholesterol and phospholipid levels of the treated rats when compared to hypercholesterolemic rats. There were significant decreases (p < 0.05) in the LPO levels of extract-treated rats. Precisely, VA at 100 and 200 mg/kg decreased the levels of plasma and PMF LPO by 38%, 42% and 35%, 45%, respectively. In addition, VA augmented the cholesterol-induced decrease in PMF glutathione levels of the rats. Taken together, these results suggest the lipid-lowering effects of VA and, probably serve as a new potential natural product for the treatment of hyperlipidemia.

Effect of silymarin and its polyphenolic fraction on cholesterol absorption in rats.

This study evaluated the influence of silymarin (SM) and polyphenolic fraction (PF) of silymarin on cholesterol absorption in rats fed on high cholesterol diet (HCD). HCD induced a remarkable increase in hepatic, plasma, VLDL and LDL cholesterol, a decrease in HDL cholesterol and an elevation in triacylglycerol (TAG) levels in plasma, VLDL and in the liver. SM and PF were administered as dietary supplements (1.0%) in HCD for 18 days. Intestinal cholesterol absorption was measured by dual-isotope plasma ratio method, which calculates percent of cholesterol absorption from the ratio of two labelled cholesterol doses, one given intragastrically (14C) and one intravenously (3H). Silymarin and PF significantly reduced cholesterol absorption in rats fed on HCD and caused significant decreases in plasma and VLDL cholesterol and content of cholesterol and TAG in the liver. The level of HDL cholesterol was significantly increased after silymarin, but not after administration of PF. The levels of TAG in plasma and VLDL were not affected by either silymarin or PF. These results suggest that the inhibition of cholesterol absorption caused by silymarin and its polyphenolic fraction could be a mechanism contributing to the positive changes in plasma cholesterol lipoprotein profile and in lipid content in liver.

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.

Effects of dietary cholestyramine on the utilisation of diets containing medium or long chain triacylglycerols by chicks.

1. The effects of graded dietary concentrations of cholestyramine (CSTY, a bile acid binding polymer), which prevents micelle formation and bile acid reabsorption, on the lipid and energy metabolism of chicks given diets containing different dietary concentrations of medium chain triacylglycerol (MCT) and long chain triacylglycerol (LCT) were investigated. 2. MCT- or LCT-supplemented diets containing 100 or 200 g oil/kg diet and 0, 10 or 20 g CSTY kg were fed to 7 d old chicks for 10 d. As dietary CSTY concentration increased, a reduction in the metabolisable energy value was observed for both dietary lipid sources. Consequently, fat and energy retentions were also reduced as the dietary CSTY content increased.

Additive hypocholesterolemic effect of psyllium and cholestyramine in the hamster: influence on fecal sterol and bile acid profiles.

Recent findings suggest that the effects of cholestyramine and psyllium in combination could be additive for cholesterol-lowering. We therefore examined the effect of both agents, alone and in combination, on lipoprotein cholesterol and neutral and acidic steroid excretion in the hamster. Animals (n = 8/group) were fed for 21 days, either a basal chow diet supplemented with 10% palm oil and 0.2% cholesterol, or one of four treatments consisting of the basal diet plus: 5.5% cellulose; 5% psyllium with 0.5% cellulose; 0.5% cholestyramine with 5% cellulose; or 5% psyllium with 0.5% cholestyramine. Psyllium and cholestyramine both had significant hypocholesterolemic effects, but in combination produced additive reductions in lipoprotein and hepatic cholesterol. Psyllium, cholestyramine, and the combination increased total bile acid excretion by 26%, 57%, and 79%, respectively. Psyllium affected only unconjugated bile acid excretion while cholestyramine also increased the excretion of conjugated and primary bile acids. Neither agent, nor the combination, affected fecal neutral sterol excretion. We conclude that, while both agents lower cholesterol by a mechanism of increased bile acid excretion, these studies indicate that psyllium does not bind bile acids in vivo and lend further support for the concomitant use of these agents for cholesterol-lowering.

Transcriptional regulation of hepatic sterol 27-hydroxylase by bile acids.

The study objective was to determine whether and to what extent sterol 27-hydroxylase, the initial step in the "acidic" pathway of bile acid biosynthesis, is regulated by bile acids. Rats were fed diets supplemented with cholestyramine (CT, 5%), cholate (CA, 1%), chenodeoxycholate (CDCA, 1%), or deoxycholate (DCA, 0.25%). When compared with paired controls, sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase specific activities increased after CT administration by 188 +/- 20% (P < 0.05) and 415 +/- 36% (P < 0.01), respectively. Similarly, mRNA levels increased by 159 +/- 14% (P < 0.05) and 311 +/- 106% (P < 0.05), respectively. Feeding CA, CDCA, or DCA decreased sterol 27-hydroxylase specific activity to 57 +/- 6, 61 +/- 8, and 74 +/- 8% of controls, respectively (P < 0.05). By comparison, the specific activity of cholesterol 7 alpha-hydroxylase decreased to 46 +/- 7 , 32 +/- 10, and 26 +/- 8% (P = 0.001). mRNA levels and transcriptional activities for sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase transcriptional activity were changed to the same extent as the specific activities after CT or bile acid feeding. We conclude that sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase are subject to negative feedback regulation by hydrophobic bile acids at the level of transcription. However, the responses of sterol 27-hydroxylase to manipulation of the bile acid pool are less prominent than those of cholesterol 7 alpha-hydroxylase. During the diurnal cycle the specific activities of sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase changed in tandem, suggesting that both may be under control of glucocorticoids.

Effect of feeding psyllium and cholestyramine in combination on low density lipoprotein metabolism and fecal bile acid excretion in hamsters with dietary-induced hypercholesterolemia.

We wished to determine the effectiveness of submaximal doses of cholestyramine and psyllium given in combination in reversing dietary-induced hypercholesterolemia in Golden Syrian hamsters, and to investigate the mechanism or mechanisms of action through which these agents together decrease plasma low density lipoprotein cholesterol (LDL-C) levels in this model. For 30 days, male hamsters were fed a cholesterol-rich cereal-based diet containing either a submaximal dose of cholestyramine (1% wt/wt) alone or in combination with psyllium (either 2 or 4%), or a high dose of cholestyramine (3%) alone. Although the greatest cholesterol-reducing action was achieved with 3% resin alone, in the animals fed one third as much cholestyramine combined with psyllium (4%) LDL-C production decreased from 288 +/- 15 to 187 +/- 17 micrograms/h per 100 g body weight, the suppression of LDL-receptor activity was almost fully reversed, plasma LDL-C levels were reduced from 90 +/- 8 to 41 +/- 5 mg/dl, and hepatic cholesterol content decreased from 17.1 +/- 1.9 to 2.4 +/- 0.1 mg/g. In the group that received 1% resin alone, the plasma LDL-C and hepatic cholesterol levels were 60 +/- 3 mg/dl and 7.2 +/- 0.6 mg/g, respectively. As compared with animals that received 1% resin alone, those fed both agents manifested higher rates of fecal bile acid excretion and lower levels of intestinal cholesterol absorption. A significant cholesterol-lowering benefit can be derived from using these nonsystemic agents in combination at lower, more tolerable doses.

Cholesterol 7 alpha-hydroxylase activity is increased by dietary modification with psyllium hydrocolloid, pectin, cholesterol and cholestyramine in rats.

Sources of dietary fiber known to alter cholesterol metabolism and/or bile acid pool size were fed to rats, and activity of the rate-limiting step in bile acid synthesis, cholesterol 7 alpha-hydroxylase, was measured. In the first experiment, semipurified diets containing 5% cellulose, psyllium hydrocolloid, pectin or oat bran as dietary fiber sources or 2% cholestyramine were fed to groups of 10 male Wistar rats for 4 wk. In the second experiment, groups of six rats were fed diets containing 5% cellulose, rice bran, oat bran or psyllium with and without 0.25% cholesterol. In the first experiment, the activity of cholesterol 7 alpha-hydroxylase (pmol.min-1.mg protein-1) was highest in the cholestyramine-treated group (95.6 +/- 3.6), followed by groups fed psyllium (35.5 +/- 3.5) or pectin (36.0 +/- 4.5), which exhibited more than twice the enzyme activity of groups fed cellulose (16.9 +/- 1.9) or oat bran (12.3 +/- 2.0). In the second experiment, feeding cholesterol resulted in significantly higher enzyme activity when cellulose (65%), oat bran (118%) and rice bran (60%) were fed, but no difference in activity was observed when cholesterol was added to the psyllium-containing diet. Higher activity of cholesterol 7 alpha-hydroxylase when pectin or psyllium rather than cellulose was fed may explain the almost twofold higher bile acid pool sizes previously reported in response to feeding either of these fibers. These data support the hypothesis that the hypocholesterolemic effect of soluble fibers is modulated through increased synthesis and therefore pool size of bile acids.

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.

Psyllium augments the cholesterol-lowering action of cholestyramine in hamsters by enhancing sterol loss from the liver.

BACKGROUND/AIMS: Psyllium hydrophilic mucilloid is a nonabsorbable soluble fiber that lowers plasma cholesterol levels in several species, including humans. However, its mechanism of action has not been fully elucidated. Therefore, using a hamster model, experiments were performed to determine whether psyllium given alone or in combination with a submaximal dose of cholestyramine blocks intestinal cholesterol absorption. METHODS: The efficiency of cholesterol absorption and concentrations of plasma and hepatic total cholesterol were measured in male hamsters fed a cholesterol-enriched chow diet (0.1%) that contained either avicel (cellulose) (7.5%), surfomer (3%), cholestyramine (1% or 3%), or psyllium (7.5%) as single agents or a fixed level of cholestyramine (1%) combined with variable levels of psyllium (2%, 4%, 6%, or 8%). RESULTS: Psyllium, cholestyramine, and surfomer, when given alone, markedly lowered plasma and hepatic cholesterol concentrations. Surfomer, and cholestyramine at the higher dose (3%), blocked cholesterol absorption by 54% and 75%, respectively, whereas psyllium had no effect. Combining psyllium with a submaximal dose of cholestyramine augmented the cholesterol-lowering action of the resin without effecting any marked change in the level of cholesterol absorption, except at the highest dose used. CONCLUSIONS: Psyllium, given either as a single agent or as an adjunct to treatment with cholestyramine, exerts a significant hypocholesterolemic effect by enhancing net negative sterol balance across the liver.

Regulation of hepatic 7 alpha-hydroxylase expression by dietary psyllium in the hamster.

Soluble fiber consistently lowers plasma total and low density lipoprotein (LDL)-cholesterol concentrations in humans and various animal models including the hamster; however, the mechanism of this effect remains incompletely defined. We performed studies to determine the activity of dietary psyllium on hepatic 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and LDL receptor expression in the hamster. In animals fed a cholesterol-free semisynthetic diet containing 7.5% cellulose (avicel) as a fiber source, substitution of psyllium for avicel increased hepatic 7 alpha-hydroxylase activity and mRNA levels by 3-4-fold. Comparable effects on 7 alpha-hydroxylase expression were observed with 1% cholestyramine. Psyllium also increased hepatic 7 alpha-hydroxylase activity and mRNA in animals fed a diet enriched with cholesterol and triglyceride. Activation of 7 alpha-hydroxylase was associated with an increase in hepatic cholesterol synthesis that was apparently not fully compensatory since the cholesterol content of the liver declined. Although dietary psyllium did not increase hepatic LDL receptor expression in animals fed the cholesterol-free, very-low-fat diet, it did increase (or at least restore) receptor expression that had been downregulated by dietary cholesterol and triglyceride. Thus, 7.5% dietary psyllium produced effects on hepatic 7 alpha-hydroxylase and LDL metabolism that were similar to those of 1% cholestyramine. Induction of hepatic 7 alpha-hydroxylase activity by dietary psyllium may account, in large part, for the hypocholesterolemic effect of this soluble fiber.

Modeling plasma lipoprotein-bile lipid relationships: differential impact of psyllium and cholestyramine in hamsters fed a lithogenic diet.

Hamsters fed a lithogenic diet become hyperlipemic with elevated very-low-density lipoprotein (VLDL) and high-density lipoprotein 2 (HDL2) cholesterol pools and develop lithogenic bile in which chenodeoxycholate (cheno) typically predominates. The relationship between these distorted lipoprotein and bile lipid profiles and gallstone induction was investigated in male Syrian hamsters fed for 5 weeks a gallstone-inducing purified diet (5% butter, 0.4% cholesterol) or the same diet supplemented with 5% psyllium or 1% cholestyramine, agents known to alter bile acid metabolism. The gallstone diet essentially doubled plasma cholesterol level, whereas psyllium decreased it to near normal, and cholestyramine to a subnormal level, while correcting the distorted distribution of cholesterol among lipoproteins. Both the gallstone diet and psyllium produced cholesterol-laden livers, in contrast to subnormal values produced by cholestyramine. Fecal bile acid excretion was increased eightfold with cholestyramine and fourfold with psyllium relative to the value produced by the gallstone diet and a literature control value. Supersaturated bile developed with the gallstone diet (lithogenic index [LI], 2.3 +/- 0.6), whereas the LI was decreased by psyllium (1.2 +/- 0.4) and cholestyramine (0.7 +/- 0.3). The gallstone diet decreased the concentration of bile acids in gallbladder bile, but greatly increased the percentage of taurochenodeoxycholic acid, whereas psyllium preferentially decreased all taurine-conjugated bile acid levels and expanded glycocholate output. Cholestyramine greatly decreased the secretion of biliary cholesterol and cheno independent of its conjugation. Accordingly, psyllium increased the glycine to taurine ratio of gallbladder bile fivefold, whereas cholestyramine did not affect this ratio, but increased the cholate to cheno ratio dramatically (25-fold) as compared with a threefold increase with psyllium. This combination of biliary lipid and bile acid alterations induced coordinated responses in the LI and the hydrophobicity index (HI) such that cholesterol gallstones developed in 11 of 12 hamsters fed the gallstone diet, whereas only one of 11 of the psyllium-fed and none of 12 cholestyramine-fed hamsters had cholesterol stones. Thus, psyllium and cholestyramine differentially increased bile acid excretion, which improved the lipoprotein profile and inhibited cholesterol gallstone formation. Both agents operated by different means to decrease biliary cholesterol secretion and the percentage of cheno, which decreased the LI and HI, respectively.

Cholestyramine as an adsorbent in acute lindane poisoning: a murine model.

STUDY OBJECTIVES: To compare the effectiveness of single-dose cholestyramine versus single-dose activated charcoal in preventing clinical toxicity after acute lindane ingestion. DESIGN: CD-1 mice received lindane by enteral (gavage) and parenteral (intraperitoneal) routes, followed by enteral administration of either cholestyramine (2.25 g/kg) or activated charcoal (2.25 g/kg), with subsequent observation for convulsions and death. MEASUREMENTS: The doses of lindane at which 50% of mice developed convulsions (CD50) and at which 50% of mice died (LD50) were established and compared among control, charcoal-, and cholestyramine-treated groups. RESULTS: For lindane administered by gavage, the differences in the CD50 and LD50 between the control and the activated charcoal groups were not statistically significant. However, a significant difference did exist in both the CD50 and the LD50 between the group receiving cholestyramine and the control group and between the cholestyramine and activated charcoal groups. After IP administration of lindane, the difference in CD50 or LD50 among control, activated charcoal, or cholestyramine groups was not significantly different. CONCLUSION: In the murine model, cholestyramine is more effective than activated charcoal in preventing absorption of lindane, thus preventing convulsions and death. These data support the need for clinical studies to determine whether cholestyramine may be a more effective treatment than activated charcoal for acute lindane ingestions in human beings.

Feeding diets containing 2% cheno- or urso-deoxycholic acid or cholestyramine to rats for two weeks alters intestinal morphology and bile acid absorption.

This study was undertaken to examine the effect of supplementing chow for 2 weeks with 2% cheno- (CDC) or ursodeoxycholic (UDC) acid or cholestyramine (CHOL) on the intestinal morphology and in vitro uptake of bile acids in adult rats. Food intake was higher in UDC and CHOL as compared with animals fed chow or CDC, or in animals pair-fed a chow-restricted diet (CRD). Body weight gain was lower in CDC and CRD but was unchanged by feeding UDC or CHOL. Jejunal mucosal surface area was similar in the five groups, although the ileal mucosal surface area was lower in UDC than in the other animals. Feeding UDC reduced the ileal uptake of cholic acid (C), taurocholic acid (TC), and glycocholic acid (GC). Feeding CDC had no effect on bile acid uptake except when compared with animals fed a chow-restricted diet. Feeding CHOL reduced the active ileal uptake of C, had no effect on the uptake of TC or GC or CDC, and was associated with increased uptake of stearic, linoleic, and linolenic acids. These effects were likely related to a direct effect of changes in the luminal bile acids rather than due to an indirect effect of the reduced food intake, since the ileal uptake of CDC and GC was greater in animals fed CDC than in those fed a chow-restricted diet with comparable weight gain. Thus, 2 weeks of feeding bile acids or bile acid binding agents may alter the form and function of the rat intestine, and as well may lead to changes in food intake and body weight gain.

Effects of corn oil and wheat brans on bile acid metabolism in rats.

High concentrations of colonic bile acids may promote tumor formation. Some studies have found that high levels of dietary fat increase fecal bile acid excretion, whereas others report no effect. Wheat bran appears to reduce fecal bile acid concentration. This study was conducted to determine the effect of different dietary fat levels and types of wheat bran on bile acid metabolism. Rats were fed diets containing either no fiber, 2% cholestyramine (CHO) or brans of hard red spring, soft white winter or durum wheat--at both a 5 or 20% fat level. Animals were fed for 7 wk, and feces were collected in the last week. Wheat bran (all types) significantly increased fecal mass approximately fourfold, and CHO significantly increased fecal mass twofold compared to the fiber-free diet. Increasing the fat level did not increase fecal bile acid excretion, nor did the addition of wheat bran. Addition of CHO, however, more than doubled it. CHO increased fecal bile acid concentration, all wheat brans decreased it and fat level had no effect. Bile acid pool size was increased slightly by fat level and cholestyramine feeding but not by wheat brans. These results indicate that fat level slightly alters bile acid metabolism but that wheat brans do not.

Regulation of cholesteryl ester metabolism in the hamster liver.

Neutral cholesteryl ester hydrolase activity has been described in the cytosolic and microsomal fraction of rat liver, but the relationship of these activities to other parameters of hepatic cholesterol metabolism is not known. We have studied this in the hamster by manipulating the flux of cholesterol across the liver by dietary modifications. A bile acid sequestrant was used to stimulate LDL receptor activity and hence flux of cholesterol into the liver. A cholesterol-rich diet caused a hypercholesterolaemia and substantial uptake of cholesterol and deposition in the liver. Hypercholesterolaemia was also induced by a saturated fat-rich diet, but in contrast this reduced the flux of cholesterol into the liver. Animals were fed these diets for 1 week and then the livers removed and enzyme activities determined. These were 3-hydroxy-3-methylglutaryl-CoA reductase, cholesterol 7 alpha-hydroxylase, acyl-CoA: cholesterol acyltransferase, microsomal cholesteryl ester hydrolase and cytosolic cholesteryl ester hydrolase. Feeding the bile acid sequestrant increased the hydrolysis of cholesteryl ester in the liver over its synthesis. In contrast, both fat feeding and cholesterol feeding caused a reduction in the relative rate of hydrolysis of cholesteryl ester compared with synthesis. This was particularly marked with the cholesterol-rich diet. These results show that the hydrolysis of cholesteryl ester in hamster liver responds to dietary manipulation in a way that reflects the needs of the cell for cholesterol or the presence of an excess. It is suggested that a metabolically significant cholesteryl ester cycle may operate in the liver to a greater extent that had previously been thought.

Effect of cholestyramine in early weaning on later response to serum and fecal steroid levels and cholesterol 7 alpha-hydroxylase activity to high-cholesterol diet in ExHC rats.

Male ExHC (exogenous hypercholesterolemic) rats were either prematurely weaned at 17 days of age or allowed to nurse until 35 days of age. The prematurely weaned rats were either fed a diet containing cholestyramine or cholestyramine-free diet until 35 days of age. Cholestyramine supplementation markedly increased fecal bile acid excretion and modified the composition. After giving a stock diet for 7 weeks, all rats received a cholesterol-enriched diet for 9 weeks. The serum cholesterol level in later time was not affected by early dietary manipulation. The activity of hepatic cholesterol 7 alpha-hydroxylase and fecal bile acid excretion at the end of the cholesterol challenge decreased in the cholestyramine-pretreated group, when compared to the normally weaned group. Fecal excretion and the ratio of the secondary (deoxycholic and lithocholic acids) to the primary (cholic and chenodeoxycholic acids) bile acids significantly decreased in the early cholestyramine-treated group. These results suggest that a modification of bile acid metabolism in early life may strongly influence the hepatic and possibly colonic bile acid metabolism in later life, when challenged with a high-cholesterol diet.