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PubMed1996

Influence of phospholipid on bile salt binding to calcium hydroxyapatite and on the poisoning of nascent hydroxyapatite crystals.

Glycine-conjugated, dihydroxy bile salts inhibit calcium hydroxyapatite (HAP) formation by binding to and poisoning nascent crystal embryos. Their taurine-conjugated counterparts bind less well to hydroxyapatite and do not inhibit its formation; but more hydrophobic, synthetic analogs of the taurine conjugated bile salts are inhibitors of hydroxyapatite formation. Because hydrophobicity is an important determinant of the ability of bile salts to inhibit hydroxyapatite crystal growth, experiments were performed to study the effect of the physiologically important mixed micelles of bile salt and phospholipid. Taurodeoxycholate/phosphatidylcholine (10:1) mixed micelles bound to HAP at lower total lipid concentrations than did pure taurodeoxycholate. At low total lipid concentrations, phosphatidylcholine (PC) binding appeared to predominate, suggesting that PC had a higher affinity than did taurodeoxycholate (TDC) for the HAP surface. Although glycodeoxycholate (3 mM) significantly (> 95%) inhibited hydroxyapatite precipitation, higher concentrations of taurodeoxycholate, either alone or mixed with phosphatidylcholine, did not affect hydroxyapatite formation. These results suggest that biliary phospholipids do not modulate the ability of bile salts to inhibit hydroxyapatite crystal growth.

Bile↗

PubMed2001

Study of partition of nitrazepam in bile salt micelles and the role of lecithin.

The effect of trihydroxy (sodium cholate and sodium glycocholate) and dihydroxy (sodium deoxycholate and sodium glycodeoxycholate) bile salt micelles on the spectrophotometric properties and on the solubility of nitrazepam in aqueous solution, at 25.0 degrees C and at ionic strength 0.1 M in sodium chloride, has been assessed. From the results obtained it was possible to calculate the partition coefficients (Kp) of nitrazepam between aqueous and micellar phases. The partition coefficients of nitrazepam have also been determined in mixed micelles of cholate or deoxycholate with lecithin (egg yolk phosphatidylcholine), which were used as a model of the gastrointestinal tract. Drug partition was found to depend on the bile acid (number of hydroxyl groups and conjugation with glycine), and our data indicate further that addition of lecithin to bile salt micelles decreases the values of the partition coefficients in the mixed micelles at physiological pH.

Bile Acids and Salts↗

PubMed1977

Activation of liver guanylate cyclase by bile salts and contaminants in crude secretin and pancreozymin preparations.

Crude preparations of secretin or pancreozymin increased and at higher concentrations decreased guanylate cyclase (GTP pyophosphate-lyase, EC 4.6.1.2) activity from soluble and particulate fractions of rat liver homogenates. Partially purified and synthetic secretin were without effect as was the biologically active octapeptide fragment of pancreozymin. The active contaminants in these preparations survived boiling, saponification, and treatment with phospholipase A, trypsin and neuraminidase C. The activity was extractable with chloroform/methanol and did not survive ashing. Eight bile salt contaminants in crude secretin were obtained with thin-layer chromatography. Two of the contaminating bile salts that increased liver particulate guanylate cyclase activity were identified as taurodeoxycholate and either glycochenodeoxycholate or glycodeoxycholate; taurocholate was inhibitory. The sodium salts of cholate, deoxycholate, chenodeoxycholate and their glycine-or taurine-conjugated forms either increased or decreased particulate and soluble rat liver guanylate cyclase activity depending upon their concentration. Thus, the previously reported stimulatory and inhibitory effects of secretin and pancreozymin preparations on guanylate cyclase activity are probable attributable to their bile salt contaminants.

Animals↗

PubMed1986

Methylprednisolone accelerates the ontogeny of sodium-taurocholate cotransport in rat ileal brush border membranes.

The effect of methylprednisolone on the postnatal maturation of taurocholate transport was studied by using isolated ileal brush border membrane vesicles. Vesicles were prepared from 14-day-old control, 14-day-old methylprednisolone-treated, and untreated 21-day-old rats. Methylprednisolone treatment resulted in a significant stimulation of taurocholate uptake by an inwardly directed Na+ gradient when compared with a choline gradient incubation. These differences occurred at 20 seconds and 1, 2, and 5 minutes of incubation (P less than 0.05). In 14-day-old controls, uptake was similar for Na+ and choline gradients. A plot of active uptake velocity vs. taurocholate concentration (0.1 to 1.0 mmol/L) in 14-day-old controls was linear and approached the abscissa, indicating the absence of active transport. Plots for methylprednisolone-treated rats showed saturability. An inwardly directed Na+ gradient stimulated initial taurocholate uptake rates by twofold at 37 degrees C (P less than 0.01), but not at 4 degrees C. Glycocholate and glycodeoxycholate inhibited Na+-stimulated taurocholate uptake by 50% (P less than 0.01) and 20% (P less than 0.05), respectively. These data indicate that pharmacologic doses of methylprednisolone accelerate the postnatal acquisition of Na+-dependent taurocholate cotransport in rat ileal brush border membranes.

Animals↗

PubMed1987

Thermodynamic and molecular determinants of sterol solubilities in bile salt micelles.

We examined, by reverse-phase high performance liquid chromatography (HPLC), the hydrophilic-hydrophobic balance of cholesterol and 12 non-cholesterol sterols and related this property to their equilibrium micellar solubilities in sodium taurocholate and sodium glycodeoxycholate solutions. Sterols investigated exhibited structural variations in the polar function (3 alpha-OH, 3 beta-OH, 3 beta-SH), nuclear double bonds (none, delta 5, or delta 7), side chain length (C27, C28, C29) and side chain double bonds (none, delta 22, or delta 24). In general, a sterol's hydrophilic-hydrophobic balance became progressively more hydrophobic (as exemplified by increasing HPLC retention values, k') with additions of side chain methyl (C28) and ethyl (C29) groups and with 3 beta-SH substitution of the 3-OH polar function. Side chain delta 22 and especially delta 24 double bonds rendered the sterols appreciably more hydrophilic, whereas a single nuclear double bond had little influence. Sterol solubilities (24 degrees C, 0.15 M Na+) were uniformly greater in 50 mM solutions of sodium glycodeoxycholate (range 0.15 to 2.5 mM) than in equimolar solutions of the more hydrophilic bile salt, sodium taurocholate (range 0.07 to 0.67 mM). For each bile salt system, a strong inverse correlation existed between micellar solubilities of sterols and their HPLC k' values, indicating that more hydrophilic sterols had greater micellar solubilities than the more hydrophobic ones. Based upon the aqueous monomeric solubilities of cholesterol (C27) and beta-sitosterol (C29) at 24 degrees C, we derived free energy changes associated with micellar binding and found that solubilization of both sterols was more energetically favored in glycodeoxycholate solutions. Although cholesterol exhibited a higher binding affinity than beta-sitosterol in glycodeoxycholate micelles, solubilization of beta-sitosterol in taurocholate micelles was more energetically favored than cholesterol by -0.6 kcal/mol. Based upon these results we offer a thermodynamic explanation for the greater micellar solubilities of more hydrophilic sterols and suggest that the high affinity, but low capacity, of a typical phytosterol for binding to trihydroxy bile salt micelles may provide a physical-chemical basis for its inhibition of intestinal cholesterol absorption.

Animals↗

PubMed1983

Influence of bile salts on the endogenous excretion of bile pigments.

Effect of the infusion of glycodeoxycholate (GDC), taurocholate (TC) and dehydrocholate (DHC) on bile flow and on bile salt, biliary lipid and bile pigment secretion, has been studied in pentobarbital-anesthetized rabbits. GDC increased bile flow the most, while DHC increased it more than TC. The different choleretic actions of these bile salts cannot be explained by means of variations in their capacity to form micelles. Only GDC and TC were able to stimulate biliary lipid secretion, which suggests that both bile salts increase the formation of mixed micelles. GDC and TC to a lesser extent increased bile pigment excretion, DHC being without effect. These results favour the hypothesis that micellar binding could be an important factor responsible for the effect of bile acids on bile pigment excretion and should not be completely ruled out.

Animals↗

PubMed1976

Metabolism of chenodeoxycholate by intestinal mucosa.

The metabolism of 14C-labeled bile salts was studied in vitro during their absorption from infused segments of rat intestine. The transported bile salts were recovered in transudates which were collected from the serosal surface of infused segments. In the jejunum, 36% of transported [14C]deoxycholate and 48% of transported [14C]chenodeoxycholate were recovered as metabolites which migrated as a seemingly single polar compound on thin layer chromatography; 52 to 72% of these metabolites could be deconjugated by cholylglycine hydrolase to yield original [14C]deoxycholate or [14C]chenodeoxycholate, respectively. The jejunum metabolized 9 times more [14C]chenodeoxycholate than the ileum (38.1 nmoles per hr per g compared with 4.2 nmoles per hr per g), despite the fact that both segments transferred the same amount of radioactivity. In contrast, [14C]cholate, [14C]glycocholate, and [14C]glycodeoxycholate were transferred intact by the jejunum, ileum, and colon. Human jejunal and rectal mucosa were able to metabolize [14C]chenodeoxycholate to polar metabolites in vitro. Polar metabolites were also found in the portal plasma and jejunal wall 20 min after the feeding of [14C]chenodeoxycholate to bile fistula rats. It is suggested that these results complicate the interpretation of in vitro experiments on absorption of dihydroxy bile salts, and that they indicate that the human small intestine may be able to metabolize chenodeoxycholate.

Animals↗

PubMed1992

Stimulatory and inhibitory effects of bile salts on rat pancreatic secretion.

The effects of various species of bile salts (chenodeoxycholate, deoxycholate, ursodeoxycholate and cholate, and their taurine and glycine conjugates) on pancreatic exocrine secretion were studied in conscious rats with external bile and pancreatic fistulae. For examination of the stimulatory effects of bile salts, bile and pancreatic juice were collected for a basal period of 90 minutes and returned to the intestine, and then solutions of bile salts (60 mmol/L) were infused intraduodenally at a rate of 1 mL/h for 2 hours. For examination of their inhibitory effects, pancreatic secretion was stimulated by exclusion of the bile and pancreatic juice; and then solutions of the bile salts were again infused intraduodenally. Chenodeoxycholate, glycochenodeoxycholate, ursodeoxycholate, deoxycholate, and its conjugates (glycodeoxycholate and taurodeoxycholate) significantly increased the fluid, bicarbonate and protein outputs, and bicarbonate concentration, with decrease in protein concentration. These increases were partially inhibited by infusion of either a cholecystokinin antagonist or secretin antibody. In contrast, cholate, taurocholate, tauroursodeoxycholate, glycoursodeoxycholate, and taurochenodeoxycholate inhibited pancreatic secretion and increase in the plasma cholecystokinin concentration produced by exclusion of bile and pancreatic juice. Thus, some bile salts, including taurocholate and taurochenodeoxycholate (major bile salts in rat bile) inhibited pancreatic secretion and cholecystokinin release, whereas some other bile salts increased pancreatic secretion via cholecystokinin release and secretin release.

Animals↗

PubMed2001

Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides.

This paper investigates the effect of starch microspheres on the absorption enhancing efficiency of various enhancer systems in formulations with insulin after application in the nasal cavity of sheep. The enhancers studied were lysophosphatidylcholine, glycodeoxycholate and sodium taurodihydroxyfusidate, a bile salt derivative. The enhancers were selected on the basis of their perceived or proven mechanism of action and worked predominantly by interacting with the lipid membrane. The bioadhesive starch microspheres were shown to increase synergistically the effect of the absorption enhancers on the transport of the insulin across the nasal membrane. Dependent on the potency of the enhancer system the increment in absorption enhancement was shown to be from 1.4 times to 5 times that obtained for the absorption enhancer in solution.

Absorption↗

PubMed1996

The effects of pH and bile salts on the binding of MeIQx to wheat bran fibre.

The effects of pH and of the bile salts, sodium cholate, chenodeoxycholate, taurocholate, deoxycholate and glycodeoxycholate on the adsorption of the heterocyclic aromatic amine mutagen and carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) onto wheat bran cell wall material have been examined. The highest binding affinity of MeIQx for bran was at pH 5.5. Binding affinity declined more rapidly with pH > 5.5 than with pH < 5.5. Bile salts in solution did not appreciably affect the binding of MeIQx to bran, but where the bile salts formed a suspension then the adsorption was reduced. Where precipitation of bile salts occurred then the free concentration of MeIQx was also reduced, indicating that MeIQx binding/immobilization could be enhanced through interaction with bile salts.

Bile Acids and Salts↗

PubMed1991

Prostaglandin protects against bile salt induced increases in proton permeation of duodenal brush border membrane.

A direct protective action of prostaglandin on luminal cell membranes was investigated by preincubating rabbit duodenal brush border membrane vesicles with prostaglandin E2 (PGE2) before incubation with bile salts. Membrane perturbation was assessed by measuring the net proton permeability (Pnet). Bile salts (deoxycholate, glycodeoxycholate, and taurodeoxycholate; 0.1-1.0 mmol/l) resulted in concentration dependent increases in Pnet: from (mean (SE] 5.42 (0.17) (n = 20) to 8.44 (0.24) x 10(-4) (n = 13) cm/s with 0.5 mmol/l deoxycholate. PGE2, 10(-8)-10(-6) mol/l, when added alone had no effect on Pnet: 5.41 (0.21) x 10(-4) (n = 14) cm/s with 10(-6) M PGE2. When duodenal brush border membranes were preincubated with PGE2, 10(-7)-10(-6) mol/l, however, the bile salt induced increase in Pnet was significantly reduced: 7.22 (0.18) x 10(-4) (n = 13) cm/s with 10(-7) mol/l PGE2 and 0.5 mmol/l deoxycholate. These findings indicate that PGE2 exerts a direct protective action on duodenal luminal membranes.

Animals↗

PubMed1986

Bile salts as endogenous digitalis like factors.

Digitalis-like factors were assayed by radioimmunoassay of digoxin in 6 bile samples obtained from patients at autopsy and in plasma from three patients with combined hepatic and acute renal failure. None of the patients received digoxin. Digitalis like factor values in bile samples were 23 to 85 nmol digoxin equivalents/1. Bile salt concentrations ranged from 38-104 mmol/l in the bile and 28-184 mumol/l in the plasma of these subjects. Bile, plasma digitalis like factor extracts and bile salt standards (0.1-3 mM) showed concentration dependent displacement of [125I]-digoxin from digoxin antibody, inhibition of hog brain Na,K-ATPase and displacement of [3H]-ouabain from Na,K-ATPase. The concentration-displacement curves suggest that bile salts could account for 50-79% of the total digitalis like factors in the six bile samples and 2-7% in the plasma of the three patients. High performance liquid chromatographic fractionation of a bile sample showed digitalis like factor peaks co-eluating with standards of tauro- and glycocholate, tauro- and glycochenodeoxycholate and tauro- and glycodeoxycholate. These bile salt peaks accounted for 78% of the total digitalis like factors in all high performance liquid chromatographic peaks in bile, but only 7% of the total digitalis like factor activity in all high performance liquid chromatographic peaks in an extract of plasma from one of the patients with hepatic and renal failure. The bile salts appear to be examples of endogenous digitalis like compounds which do not act by simple competitive ligand binding to antidigoxin antibody and Na,K-ATPase. They make an important contribution to digitalis like factor activity in bile, but not in plasma.

Acute Kidney Injury↗

PubMed1986

Effects of bile salts on pancreatic secretion in rabbits: ursodeoxycholate infused into the duodenum stimulates pancreas.

The effects of six species of bile salts, deoxycholate, ursodeoxycholate, glycodeoxycholate, tauroursodeoxycholate, chenodeoxycholate, and cholate (DCA, UDCA, GDC, TUDC, CDCA, CA), on pancreatic secretion were examined in anesthetized rabbits. When bile salts were infused intraduodenally, only UDCA significantly increased the pancreatic juice flow and bicarbonate output, whereas the increase in protein output was only transient. In contrast, UDCA infused intravenously did not affect the pancreatic secretion. Furthermore, none of the other bile salts, either intraduodenally or intravenously administered, had any significant effect on pancreatic exocrine function. Pancreatic responses to the intraduodenally administered UDCA in terms of fluid, bicarbonate, and protein secretion were similar to those of secretin infused intravenously. Thus, it was suggested that UDCA infused intraduodenally stimulates pancreatic secretion, possibly via the release of a secretin-like substance(s) from the duodenal wall.

Animals↗

PubMed1992

The influence of bile salts on small intestinal motility in the guinea pig in vitro.

The effect of bile salts on intestinal motility is unclear. In the current study, isometric contractions of the guinea pig terminal ileum were examined in vitro. Dose-response curves to known agonists cholecystokinin (CCK), bethanechol, and KCl were constructed alone and in the presence of atropine (10(-6) mol/L), tetrodotoxin (10(-6) mol/L), and different bile salts, namely, taurodeoxycholate, tauroursodeoxycholate, taurocholate, glycodeoxycholate, and glycoursodeoxycholate. These bile salts, at levels as low as 5 and 50 mumol/L, significantly depressed (P less than 0.05) CCK-induced contractions throughout the dose-response curves and were concentration dependent. This depressant effect was not dependent on the bile salt species or any apparent physicochemical differences between them. The inhibitory effect was also specific for certain agonists such as CCK (the action of which was partially mediated by cholinergic nerves, being depressed by atropine and abolished by tetrodotoxin), field stimulation, and nicotine. Bile salts had no effect on either bethanechol- or KCl-induced contractions. Such bile salt inhibition of excitatory, cholinergic, enteric neurons may slow transit through the ileum, enhancing the time for absorption and conserving the bile salt pool.

Animals↗

PubMed2003

Solubilization of carotenoids from carrot juice and spinach in lipid phases: II. Modeling the duodenal environment.

We have been investigating the factors determining the bioavailability of carotenoids from vegetables. The previous paper [Rich, G.T., Bailey, A.L., Faulks, R.M., Parker, M.L., Wickham, M.S.J., and Fillery-Travis, A. (2003) Solubilization of Carotenoids from Carrot Juice and Spinach in Lipid Phases: I. Modeling the Gastric Lumen, Lipids 38, 933-945] modeled the gastric lumen and studied the solubilization pathway of carotenes and lutein from carrot juice and homogenized spinach to oil. Using the same vegetable preparations, we have extended our investigations to solubilization pathways potentially available in the duodenum and looked at the ease of solubilization of carotenes and lutein within simplified lipid micellar and oil phases present within the duodenum during digestion. Micellar solubility of raw spinach carotenoids was low and was enhanced by freezing, which involved a blanching step. The efficiency of solubilization of carotenoids in glycodeoxycholate micelles decreased in the order lutein(carrot) > lutein(blanched-frozen spinach) > carotene(blanched-frozen spinach) > carotene(carrot). Frozen spinach carotenoids were less soluble in simple micelles of taurocholate than of glycodeoxycholate. The results comparing the solubility of the carotenoids in mixed micelles (bile salt with lecithin) with simple bile salt micelles are explained by the relative stability of the carotenoid in the organelle compared to that in the micelle. The latter is largely determined by the polarity of the micelle. Below their critical micelle concentration (CMC), bile salts inhibit transfer of carotenoids from tissue to a lipid oil phase. Above their CMC, the bile salts that solubilize a carotenoid can provide an additional route to the oil from the tissue for that carotenoid by virtue of the equilibrium between micellar phases and the interfacial pathway. Mixed micellar phases inhibit transfer of both carotenoids from the tissue to the oil phase, thereby minimizing this futile pathway.

Bile Acids and Salts↗

PubMed1983

Biliary protein output by isolated perfused rat livers. Effects of bile salts.

The output of proteins into bile was studied by using isolated perfused rat livers. Replacement of rat blood with defined perfusion media deprived the liver of rat serum proteins (albumin, immunoglobulin A) and resulted in a rapid decline in the amounts of these proteins in bile. When bovine serum albumin was incorporated into the perfusion medium it appeared in bile within 20 min and the amount in the bile was determined by the concentration of the protein in the perfusion medium. The use of a defined perfusion medium also deprived the livers of bile salts and the amounts of these, and of plasma-membrane enzymes [5'-nucleotidase (EC 3.1.3.5) and phosphodiesterase I], in bile declined rapidly. Introduction of micelle-forming bile salts (taurocholate or glycodeoxycholate) to the perfusion medium 80 min after liver isolation markedly increased the output of plasma-membrane enzymes but had no effect on the other proteins. The magnitude of this response was dependent on the bile salt used and its concentration in bile; there was little effect on plasma-membrane enzyme output until the critical micellar concentration of the bile salt had been exceeded in the bile. A bile salt analogue, taurodehydrocholate, which does not form micelles, did not produce the enhanced output of plasma-membrane enzymes. This work supports the view that the output of plasma-membrane enzymes in bile is a consequence of bile salt output and also provides evidence for mechanisms by which serum proteins enter the bile.

5'-Nucleotidase↗

PubMed1990

Bile salt-induced increases in duodenal brush-border membrane proton permeability, fluidity, and fragility.

Rabbit duodenal brush-border membrane vesicles were treated in vitro with deoxycholate, glycodeoxycholate, or taurodeoxycholate. Intravesicular [14C]glucose space at equilibrium, 0.54 microliters/mg protein, was reduced by exposure to the three bile salts in a concentration (0.1-5.0 mM)-dependent manner, equatable with increased membrane fragility. Net proton permeability (Pnet), determined by acridine orange fluorescence quenching, was increased from 6.3 x 10(-4) cm/sec in untreated vesicles, by approximately 120, 150, and 170%, by treatment with bile salts at 0.1, 0.5 and 1.0 mM, respectively. The three bile salts were equipotent. The increases in membrane fragility and Pnet were not accompanied by significant increases in membrane fluidity, as assessed from steady-state and time-resolved diphenylhexatriene fluorescence anisotropy. The data demonstrate direct effects of bile salts on duodenal apical membrane fragility and proton permeability that are likely to be early events in bile salt-induced mucosal damage.

Animals↗

PubMed2002

Solubilization of drugs by physiological mixtures of bile salts.

PURPOSE: The solubilization of a number of steroids was determined in bile salt simple micelles and a bile salt/phospholipid micellar system to provide a better basis to predict the extent of drug solubilization in vivo. METHODS: Excess solid drug was dispersed in taurodeoxycholate or mixed micelle solutions prepared with fixed mole ratios of taurocholate, taurodeoxycholate, taurochenodeoxycholate, glycodeoxycholate, glycocholate, and glycochenodeoxycholate with egg phosphatidylcholine. Drug concentrations were determined from the absorbance following centrifugation. Using NMR spectroscopy, the diffusivities of the simple and mixed micelles were 2 x 10(-6) and 8 x 10(-7) cm2/s, respectively. RESULTS: From the change in the concentration of drug in solution with a change in the lipid concentration, the solubilization ratio (SR) was calculated. The SR and aqueous solubility were used to calculate the micelle/aqueous partition coefficients (Km/w). Km/w was correlated with octanol/water partition (Po/w) for the TDC and mixed micelle data sets with correlation lines of logKm/w = 0.74logPo/w + 1.55 (r2 = 0.91) and logKm/w = 0.61 logPo/w + 2.44 (r2 = 0.95), respectively. CONCLUSIONS: With such data, a refined, predictive relationship between the in vitro and the in vivo solubilization with additional information concerning the bile salt/lipid concentration in the human intestine appears possible.

Bile Acids and Salts↗