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PubMed1995

Interaction between Cu2+ ions and cholic acid derivatives followed by polarography.

Interaction of bile salts with Cu2+ ions in unbuffered systems containing 0.15 M NaNO3 was followed by measuring polarographic limiting currents and half-wave potentials. Whereas taurocholate forms neither soluble complexes nor compounds of limited solubility, cholate, glycocholate, and dehydrocholate from both soluble complexes and slightly soluble salts of copper(II) with small aggregates of bile salts. The stability of soluble complexes is comparable for cholates, dehydrocholates, acetates, and acetylglycinates, but smaller for glycocholates. The solubility of the copper(II) salts with small aggregates decreases in the sequence: glycocholate > cholate >> dehydrocholate. It is proposed that these salts are formed by interaction of a copper(II) ion with two carboxylic groups located on the small aggregate in a sufficiently small distance. In the presence of excess cholate the precipitated copper(II) salts are dissolved. It is assumed that at high bile salt concentrations, where precipitates are not observed, larger aggregates are formed that have free carboxylate groups, which increase their solubility in aqueous solutions. For glycocholate, within the accessible concentration range and within the time-frame used (24 h for the establishment of the equilibrium), the formation of such larger aggregates was not observed, even when its "cmc" is comparable with that of cholate. The absence of formation of larger aggregates for dehydrocholate parallels its tendency not to form "micelles".

Carboxylic Acids↗
PubMed1982

A comparative study of the effect of various detergents on the structure and function of sarcoplasmic reticulum vesicles.

The effects produced by the detergents Triton X-100, sodium dodecylsulphate and sodium cholate on sarcoplasmic reticulum vesicles have been comparatively studied. In all cases, maximal effects are found 5 min after detergent addition. Triton X-100 and SDS are approximately ten times more effective than cholate in protein and phospholipid solubilization. Both Triton X-100 and SDS maintain Ca++ accumulation in SR vesicles at detergent concentrations below 10(-3) M; higher concentrations cause a strong inhibition. On the other hand, cholate produces a gradual inhibition of Ca++ accumulation in the concentration range between 10(-4) M and 2.5 X 10(-2) M. Triton X-100 and SDS produce a gradual solubilization of the specific Ca++-ATPase activity up to a 10(-3) M detergent concentration, above which a strong inactivation occurs, while the enzyme solubilization increases with the presence of cholate in the whole concentration range under study. The different behaviour of sodium cholate, when compared to SDS or Triton X-100, is discussed in relation to the surfactant molecular structures. The possibility of membrane lysis and reassembly in the presence of some detergents is also considered.

Animals↗
PubMed1979

Colonic absorption of unconjugated bile acids: perfusion studies in man.

Colonic absorption of three major unconjugated bile acids--cholate, chenodeoxycholate, and deoxycholate--was measured under steady-state conditions using a technique of colonic perfusion in healthy volunteers. Aqueous solutions at pH 8.0 and varying in concentration from 1 mM to 10 mM were used. The rate of chenodeoxycholate absorption averaged nine times that of cholate absorption; deoxycholate absorption was somewhat less than that of chenodeoxycholate absorption, averaging six times that of cholate. At concentrations below 5 mM, the rate of absorption of bile acids was directly proportional to concentration, so that "clearance" could be calculated. Clearance values for a 1-mM solution (ml/min/colon, mean +/- SE) were: chenodeoxycholate, 9.84 +/- 1.0; deoxycholate, 7.0 +/- 1; and cholate, 0.82 +/- 0.10. Since absorption was proportional to concentration in the lumen, and was more rapid for the dihydroxy acids, the major mechanism of absorption was thought to be passive nonionic diffusion. Maximal rates of bile acid absorption were calculated from a 1-mM solution and found to be as high as 4.2 g/day for chenodeoxycholate, 3.2 g/day for deoxycholate, and 0.5 g/day for cholate, and the rate would be still greater for more concentrated solutions. Colonic absorption may contribute significantly to conservation of the dihydroxy bile acid pool, especially in conditions of bile acid malabsorption.

Bile Acids and Salts↗
PubMed2001

Human intestinal cell monolayers are preferentially sensitive to disruption of barrier function from basolateral exposure to cholic acid: correlation with membrane transport and transepithelial secretion.

Unconjugated bile acids such as cholic acid cause diarrhoea, mucosal irritation and toxicity. We sought to define the mechanism of cholate permeation across intestinal mucosal cells to understand how cellular exposure and accumulation are deleterious to mucosal function. Human intestinal Caco-2 and T84 cell monolayers were prepared by high-density seeding and cultured for >14 days on permeable culture supports. Cholate transport and cellular accumulation were determined using [3H]cholic acid. Epithelial barrier function was assessed by measuring transepithelial electrical resistance (Rt) and [14C]mannitol fluxes. Exposure of Caco-2 epithelia to serosal cholate caused a dose- and time-dependent disruption of barrier function. Apical exposure was without disruptive effect. Similar responses were observed for T84 epithelia. Cholate was preferentially accumulated across the basolateral surfaces in both Caco-2 and T84 cells, but was subject to active transepithelial secretion in Caco-2 monolayers only. Net secretion was substantially reduced by ATP depletion, showed saturation kinetics, and was subject to competitive inhibition by other bile acids. Cholate secretion was also sensitive to inhibition by the leukotriene antagonist MK-571 but not by digoxin, suggesting that MRP2, not MDR1, was responsible. RT-PCR and Western blotting confirmed MRP2 expression in Caco-2 epithelia but indicated its apparent absence from T84 cells.

Absorption↗
PubMed1991

Sequential use of detergents for solubilization and reconstitution of a membrane ion transporter.

Solubilization and reconstitution of the cardiac sarcolemmal Na+/Ca2+ exchanger by use of the anionic detergent cholate and its application for reconstitution of the exchanger following solubilization with zwitterionic or nonionic detergents is described. Solubilization and reconstitution with cholate provided a 32.6-fold enrichment of Na+/Ca2+ exchange activity over sarcolemmal vesicles (5.2 to 170 nmol/mg/s) with 202% recovery of total activity. In combination with asolectin, the cholate dilution technique (H. Miyamoto and E. Racker, J. Biol. Chem. 255, 2656, 1980) offers a rapid and simple means for reconstitution and provides good recovery of total and specific Na+/Ca2+ exchange activity. However, the use of anionic detergents for solubilization precludes the use of certain chromatographic procedures for protein purification. Conversely, nonionic and zwitterionic detergents permit effective use of available chromatographic techniques, but can be troublesome during reconstitution. We have combined the advantages of solubilization with nonionic and zwitterionic detergents with the advantages of reconstitution by cholate dilution. Reconstitution of the exchanger, after solubilization with 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propanesulfonate (Chaps) or n-octyl-beta-D-glucoside, was accomplished by the addition of a cholate/asolectin medium followed by dilution. Na+/Ca2+ exchange activity was enriched 30.7-fold with 196% recovery with Chaps and 34.1-fold with 204% recovery with n-octyl-beta-D-glucoside. The presence of Chaps was found to shift the optimal asolectin concentration for reconstitution from 15 mg/ml (cholate alone) to 25 mg/ml. In addition, pelleting of proteoliposomes subsequent to reconstitution resulted in greatest recovery of total activity when volumes were kept below 1.0 ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Studies on the role of the oligomeric state and subunit III of cytochrome oxidase in proton translocation.

Anion-exchange fast protein liquid chromatography in the presence of lauryldimethylamine N-oxide (LDAO) was introduced to separate cytochrome oxidase into different complexes that either did or did not contain subunit III. Both kinds of enzyme complex exhibited H+ translocation after reconstitution into phospholipid vesicles, but with a significantly (approx. 50-60%) reduced H+/e- ratio as compared with unchromatographed enzyme. The anion-exchange FPLC fractions of the enzyme (with or without subunit III) sedimented more slowly than the control enzyme upon sucrose gradient centrifugation in the presence of cholate and a high potassium phosphate concentration. When the control enzyme was subjected to the sucrose gradient centrifugation in the presence of LDAO or Triton X-100, instead of cholate, one band containing all subunits was observed, which sedimented slowly like the FPLC fractions. Transfer of this band to cholate medium, and reapplication on the sucrose gradient (with cholate), yielded both a slow- and a fast-migrating band after centrifugation. Enzyme complexes that sedimented slowly or rapidly in the sucrose gradients revealed longer and shorter elution times, respectively, in gel filtration FPLC. This suggests that these complexes corresponds to monomers and dimers of cytochrome oxidase. Solubilization of proteoliposomes and subsequent sucrose gradient centrifugation in cholate yielded one fast-migrating band for the untreated enzyme, but both a fast- and a slow-migrating band for the anion-exchange FPLC-treated enzyme, which was exclusively slow-migrating before reconstitution into liposomes. It is suggested that dimerisation of monomeric cytochrome oxidase may be favoured when the enzyme encounters a membranous milieu, and that the dimeric structure might be necessary for proton translocation.

Animals↗
PubMed1988

Comparative investigations on the uptake of phallotoxins, bile acids, bovine lactoperoxidase and horseradish peroxidase into rat hepatocytes in suspension and in cell cultures.

Two alternative uptake mechanisms for phallotoxins by liver cells are debated: carrier-mediated uptake and receptor-mediated endocytosis. We have compared the properties of hepatocellular uptake of the phallotoxins, phalloidin and demethylphalloin, with the uptake of cholate as a substrate for carrier-mediated uptake and compared with iodinated bovine lactoperoxidase or iodinated horseradish peroxidase, as the latter are known to be taken up by vesicular endocytosis. Uptake of phallotoxins and [14C]cholate uptake into isolated hepatocytes is independent of extracellular calcium but inhibited by A23187 or by monensin. Uptake of bovine lactoperoxidase strictly depends on external Ca2+, was insensitive to A23197 and was not inhibited by monensin. No mutual uptake inhibition between phalloidin or cholate and peroxidases was seen, indicating independent permeation pathways in hepatocytes. However, high concentrations of cytochalasin B inhibited the uptake of either phalloidin, cholate or bovine lactoperoxidase. Horseradish peroxidase uptake, which was taken as an indicator for fluid pinocytosis, was low in isolated hepatocytes and could not account for the amount of phalloidin or cholate taken up. In cultured rat hepatocytes, uptake of phallotoxins decreased within 1 day to 10% of the uptake seen in freshly isolated hepatocytes. The results indicate different mechanisms for hepatocellular phallotoxin/bile-acid uptake and peroxidase internalization. As monolayer cultures of hepatocytes rapidly lost the carrier-mediated uptake of phallotoxins and bile acids, freshly isolated hepatocytes might be a more suitable experimental model than cultured cells for kinetic studies on this transport system.

Amanitins↗
PubMed1991

Reconstitution experiments provide no evidence for a role for the 53-kDa glycoprotein in coupling Ca2+ transport to ATP hydrolysis by the (Ca(2+)-Mg2+)-ATPase in sarcoplasmic reticulum.

The sarcoplasmic reticulum (SR) of skeletal muscle contains a 53 kDa glycoprotein of unknown function, as well as the (Ca(2+)-Mg2+)-ATPase. It has been suggested that the glycoprotein couples the hydrolysis of ATP by the ATPase to the transport of calcium. It has been shown that if SR vesicles are solubilized in cholate in media containing low K+ concentrations followed by reconstitution, then vesicles are formed containing the glycoprotein and with ATP hydrolysis coupled to Ca2+ accumulation, as shown by a large stimulation of ATPase activity by addition of A23187. In contrast, if SR vesicles are solubilized in media containing a high concentration of K+, then the vesicles that are produced following reconstitution lack the glycoprotein and show low stimulation by A23187 (Leonards, K.S. and Kutchai, H. (1985) Biochemistry 24, 4876-4884). We show that the effect of K+ on reconstitution does not follow from any changes in the amount of glycoprotein but rather from an effect of K+ on the detergent properties of cholate. In low K+ media, the cmc of cholate is high, cholate is a relatively poor detergent and incomplete solubilization results in 'reconstitution' of vesicles with the correct orientation of ATPase molecules. In high K+ media, the cmc of cholate is reduced and more complete solubilization of the SR leads to a true reconstitution with the formation of vesicles with a random orientation of ATPase molecules. The experiments provide no evidence for an effect of the glycoprotein on the (Ca(2+)-Mg2+)-ATPase.

Adenosine Triphosphate↗
PubMed1980

Solubilization, partial purification and characterization of rat liver microsomal diacylglycerol acyltransferase.

The diacylglycerol acyltransferase (EC 2.3.1.20) activity of rat liver microsomes was solubilized with deoxycholate, cholate, and Triton X-100. The cholate-solubilized activity proved to be more stable than the deoxycholate-solubilized activity. Cholate caused less interference with the diacylglycerol acyltransferase assay than Triton X-100. The cholate-solubilized activity was purified 3- to 4-fold by Sepharose 4B chromatography, and could be separated from most of the cholate-solubilized protein by centrifugation in a 10--20% sucrose gradient. The purification led to an overall purification of 9-fold with a recovery of 80%. The gradient fractions were analyzed for protein, RNA, and phospholipid content as well as for several enzyme activities of glycerolipid biosynthesis. The partially purified fractions were delipidated and activity was stimulated 5-fold by the addition of sonicated microsomal phospholipids. The soluble, gradient-puridied diacylglycerol acyltransferase activity was strongly dependent on added magnesium.

Acyltransferases↗
PubMed1987

Absorption of protein via the intestinal wall. A quantitative model.

Intact, biological active insulin and pancreatic RNase can be absorbed from the intestinal lumen into the blood circulation. The absorption is dependent on the addition of bile acid (sodium cholate) and proteinase inhibitor. The quantitative absorption of insulin and pancreatic RNase has been demonstrated in an in situ model. The amount of insulin absorbed after 30 min from the ileum to the mesenteric vein was 0.025% of the initial amount. Sodium cholate (10 mg/ml) and 3000 KIU/ml aprotinin enhanced this absorption by 30 times. The amount of pancreatic RNase which was absorbed from the ileum to the blood was 0.002% of the initial amount during 30 min. Sodium cholate (10 mg/ml) and 3000 KIU/ml aprotinin increased the absorption by a factor of 200. No damage occurred to the intestine during the experimental procedures. The sieving characteristics of the intestinal wall were not altered by the presence of sodium cholate and proteinase inhibitor in the intestinal lumen. These results suggest that sodium cholate and proteinase inhibitors can facilitate the absorption of intact, biologically active proteins across the intestinal wall.

Animals↗
PubMed1990

2-Fluoro-beta-alanine, a previously unrecognized substrate for bile acid coenzyme A:amino acid:N-acyltransferase from human liver.

Our laboratory has demonstrated recently that conjugates of 2-fluoro-beta-alanine (FBAL) and bile acids are the major biliary metabolites of 5-fluorouracil (FUra) in cancer patients. Bile acids are normally conjugated with glycine or taurine, and therefore the identification of the FBAL-bile acid conjugates suggested that FBAL may also be a substrate for the bile acid conjugating enzyme, bile acid CoA:amino acid:N-acyltransferase. Enzyme activity detected using glycine and taurine as substrates was purified 8-fold from human liver cytosol using a DEAE-cellulose column. This preparation when tested for its activity towards beta-alanine and FBAL using cholyl CoA as the bile acid substrate only catalyzed the formation of FBAL-cholate. beta-Alanine was not a substrate. Confirmation of FBAL-cholate as the enzymatic product was demonstrated by (1) coelution of the product of this reaction on HPLC with authentic FBAL-cholate, (2) specific hydrolysis of this product by cholylglycine hydrolase, and (3) molecular weight of the product (497) being identical to that of the authentic FBAL-cholate. Kinetic experiments demonstrated that the enzyme had an affinity for FBAL (Km 1.45 mM) comparable to taurine (Km 1.32 mM), but greater than glycine (Km 6.45 mM). Formation of FBAL-cholate was inhibited competitively by taurine (Ki 1.27 mM) and glycine (Ki 4.47 mM), suggesting that a single enzyme is responsible for conjugation of glycine, taurine and FBAL with bile acids. These data indicate that the formation of the FBAL-bile acid conjugates in patients receiving FUra results from high affinity of the bile acid conjugating enzyme for FBAL.

Acyltransferases↗
PubMed1991

Mechanism of inhibition of hepatic bile acid uptake by amiloride and 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS).

The mechanisms by which amiloride and 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS) inhibit hepatic uptake of cholate and taurocholate (TC) were investigated in isolated rat hepatocytes. Amiloride inhibited Na(+)-dependent uptake of cholate and TC only when hepatocytes were preincubated with amiloride, indicating an indirect effect of amiloride. Time-dependent studies showed that the inhibition of bile acid uptake was associated with a parallel increase in intracellular Na+ concentration ([Na+]i). Although amiloride decreased intracellular pH, this decrease preceded amiloride-induced inhibition of bile acid uptake and increase in [Na+]i. Amiloride inhibited bile acid uptake, decreased membrane potential, and increased [Na+]i with comparable concentration dependency. DIDS inhibited Na(+)-dependent uptake of cholate and TC non-competitively. Neither DIDS nor amiloride inhibited Na(+)-independent uptake of cholate and TC. These results indicate that amiloride inhibits Na(+)-dependent cholate and TC uptake by decreasing the transmembrane Na(+)-gradient, and further support the hypothesis that two different transporters may be involved in hepatic bile acid uptake by Na(+)-dependent and Na(+)-independent mechanisms.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1983

Is normal pregnancy cholestatic?

Fasting and 2-h postprandial concentrations of conjugated cholate and conjugated chenodeoxycholate in plasma were measured sequentially through normal pregnancy in a consecutive series of 26 women. Fasting concentrations of cholate significantly increased by 34 weeks and remained so up to 6 weeks post partum. No significant changes were found in fasting or 2-h postprandial concentrations of chenodeoxycholate. Postprandial concentrations of cholate were significantly higher post partum than at 22 weeks of pregnancy. The ratio of fasting cholate: chenodeoxycholate rose from 1.1 : 1.0 at 20 weeks to 1.9 : 1.0 at 38 weeks. In the third trimester, concentrations of conjugated cholate were elevated above the laboratory reference range in 5 of these 26 normal pregnancies. It is concluded that normal pregnancy is associated with mild sub-clinical cholestasis.

Adult↗
PubMed1992

Evidence for an ATP-driven H(+)-pump in the plasma membrane of the bovine corneal epithelium.

In a highly enriched plasma membrane fraction isolated from the bovine corneal epithelium, MgATP dependent intravesicular acidification was identified by measuring Acridine Orange quenching. The rate of acidification was increased 2.7-fold by pre-exposure of the membranes to 1% cholate which was subsequently removed by Sephadex G-50 column chromatography. However, in a lysosomal fraction whose enrichment with respect to the homogenate was 82-fold in N-acetyl-beta-D-glucosaminidase, cholate pre-exposure had no significant effect on the rate of intralysosomal acidification. This difference is assumed to reflect reorientation by cholate of the H(+)-pump's normally inaccessible ATP-binding site in right-side-out vesicles of the plasma membrane-enriched fraction to a configuration in which this site becomes accessible to externally added ATP. In contrast, the ATP-binding site of the H(+)-pump in the lysosomal fraction is completely exposed to the exterior even in the absence of cholate treatment. The characteristics of the H(+)-pump in the plasma membrane fraction was subsequently determined using cholate-pretreated membrane vesicles. The rank order of nucleotide support of the H(+)-pump activity was: ATP >> GTP > ITP. However, UTP and CTP were totally inactive. The pump is electrogenic because the activity of the pump was enhanced in voltage-clamped membrane vesicles. Substitution of Mg2+ with Mn2+ did not change the acidification rate but Co2+ only partly activated whereas Ca2+ and Zn2+ were ineffective as activators. The H(+)-pump was relatively unaffected by oligomycin, azide or vanadate but completely inhibited by 10 microM NEM or NBD-Cl and 92% inhibited by 20 microM DCCD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1983

Reconstitution of a partially purified Na+-independent D-glucose transport system from rat jejunal basolateral membranes.

1. Basolateral membranes of rat small intestine were first solubilized in a 0.6% cholate buffer and then the insoluble fraction was reextracted with a 1.2 or 1.6% cholate buffer. 2. Proteoliposomes reconstituted from the 1.2 or 1.6% cholate-extracted membrane fraction demonstrated characteristic Na+-independent D-glucose transport of the native basolateral membrane vesicles: inhibitable by mercuric chloride and D-galactose. 3. To further purify this D-glucose transport system, the 1.6% cholate-extracted membrane fraction was chromatographed on either hydroxylapatite, concanavalin A, wheat-germ lectin or castor bean lectin-120 affinity gels. 4. Proteoliposomes reconstituted from the membrane proteins adsorbed on hydroxylapatite and subsequently passed through agarose-castor bean lectin-120 showed a 12-fold enrichment of Na+-independent D-glucose transport activity over that of the native membrane vesicles. 5. SDS-electrophoretic analysis showed that the protein composition of the hydroxylapatite-castor bean lectin-120 treated fraction was much simpler than that of both 1.6% cholate-extracted fraction and the native membrane vesicles.

Animals↗
PubMed1985

Modified somatostatins as inhibitors of a multispecific transport system for bile acids and phallotoxins in isolated hepatocytes.

Somatostatin inhibits the uptake of phallotoxins and of cholic acid in isolated liver cells in a concentration-dependent manner. The inhibition is independent on the preincubation period and fully reversed by switching to a somatostatin-free buffer. Concentrations needed for 50% inhibition decreased 30-80-fold when somatostatin was modified by variation of its amino acid sequence. Some cyclic hexa- or penta-peptides inhibited both kinds of transport more strongly as the original (14 amino acid) somatostatin did. Three of the analogs showed a 2-3-fold higher potency than the others. The most potent compound (cyclo (Phe-Thr-Lys-Trp-Phe-D-Pro) 1 was studied in detail. The IC50 for the initial uptake of phallotoxin (6 microM) or of cholate (6 microM) was 1.5 or 3 microM, respectively. 1 inhibited the uptake of cholate in a competitive manner. The inhibition was independent on the preincubation time, but in contrast to somatostatin not fully reversible after a preincubation of 35 min. Somatostatin as well as its analogs prevented binding of isothiocyanatobenzamido [3H]cholate (an affinity label of the cholate transporter) to isolated plasma membranes from rat liver. The transport inhibition of cholate uptake is unlikely to be a hormonal effect of somatostatin, because the concentrations needed are approx. 1000-fold higher than circulating levels; however, it is apparently possible to increase the inhibitory potency on the tested transport system by modification of the sequence without increase of the well-known hormonal effects (Designing Activity and Receptor-Selectivity in Cyclic Peptide Hormone Analogs, Kessler, H., 18th Ervag Conference, Brussels, 1983).

Amanitins↗
PubMed1995

Change of zonal bile acid processing after partial hepatectomy in the rat.

The aim of this study was to analyze whether partial hepatectomy alters functional liver heterogeneity with respect to bile acid processing. One, 5 and 21 days after liver resection (approximately 80% of liver mass) in male Sprague-Dawley rats (300-400 g), isolated livers were perfused in either the antegrade or the retrograde direction, respectively, with 32 nmol cholate/min per g liver. Uptake, metabolism and biliary secretion kinetics were determined by bolus injection of 14C-cholate. Uptake and biliary recovery (within 30 min) of cholate were > 90% in all groups. One day postresection, liver mass had already doubled and it regenerated to over 80% 5 days after resection. Serum bile acid concentration increased rapidly, peaking 6 h after resection (176.7 +/- 28.5 mumol/l) (mean +/- SEM). Twenty-one days after resection it fell to control values (23.2 +/- 3.8 mumol/l). T25 (T50), the time (min) necessary to excrete 25% (50) of the bile acid load into bile, was strikingly different between periportal and pericentral cells of controls (1.8 vs 5.7 and 3.4 vs 8.1). Five days after resection this difference became smaller (1.4 vs 2.9 and 2.8 vs 5.5) due to accelerated biliary cholate secretion in pericentral cells. Pericentral cells of controls metabolized cholate more extensively to taurocholate (approximately 83%) and glycocholate (approximately 13%) than periportal cells of controls (65%, 10%), leading to a 5-fold higher proportion of unmetabolized cholate in periportal than pericentral cells (25% vs 5%). Five days after resection the percentage of taurocholate decreased significantly at the expense of an increased formation of glycocholate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Griseofulvin and ketoconazole solubilization by bile salts studied using fluorescence spectroscopy.

The capacity of solubilization of the five physiological bile salts: cholate, deoxicholate, hiocholate, quenodeoxicholate and taurocholate were assayed on two low aqueous soluble antimicotic agents: griseofulvin and ketoconazole. The fluorescence emission of these antimicotic agents was used as tool to study their solubilization in bile salts micelle. Griseofulvin enhanced its fluorescence and shifted to the blue in the presence of bile salts micelles. The shift was dependent of the polarizability of the micelle zone where the antimicotic is located. Cholate and deoxicholate showed a good solubilization capacity for griseofulvin: 321 mol and 394 mol surfactant per mol of antimicotic, respectively. These values decreased in the presence of NaCl in agreement with a compactness of the micelle due to an electrostatic repulsion decreasing between the bile salts monomer negatively charged. The imidazole and piperazine rings present in the ketoconazole molecule give to this the capacity of fluorescence emission with two vibronic bands at 364 nm and 382 nm, respectively. The solubilization in cholate micelle induced an increase in the band at 382 nm, while deoxicholate induced the opposite effect, suggesting a strong intercation between the polar groups of ketoconazole molecule (imidazole and piperazine rings) and the (-)OH of these bile salts. The solubilization capacities were 47 mol and 117 mol surfactant per ketoconazole mol for cholate and deoxicholate, respectively. The other bile salts assayed did not show any appreciable solubilization capacity. Ketoconazole and griseofulvin solubilized in micelles of cholate and deoxicholate were stable during the thermal recycling treatment for over 100 days.

Bile Acids and Salts↗