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PubMed2002

Cholate-induced dimerization of detergent- or phospholipid-solubilized bovine cytochrome C oxidase.

Bovine heart cytochrome c oxidase (CcO), solubilized by either nonionic detergents or phospholipids, completely dimerizes upon the addition of bile salts, e.g., sodium cholate, sodium deoxycholate, or CHAPS. Bile salt induced dimerization occurs whether dodecyl maltoside, decyl maltoside, or Triton X-100 is the primary solubilizing detergent or the enzyme is dispersed in phosphatidylcholine, phosphatidylethanolamine, or mixtures thereof. In each case, complete CcO dimerization can be verified by sedimentation velocity and sedimentation equilibrium after correction for bound detergent and/or phospholipid. The relative concentration of the bile salt is critical for production of homogeneous, dimeric CcO. For example, enzyme solubilized by 2 mM detergent requires an equal molar concentration of sodium cholate. Similarly, enzyme dispersed in 20 mM phospholipid requires 50 mM sodium cholate, concentrations that are commonly used to reconstitute CcO into small unilamellar vesicles. Bile salts do more than just stabilize dimeric CcO and prevent detergent-induced dissociation into monomers. They are able to completely reverse detergent-induced monomerization and cause completely monomeric CcO to reassociate. Dimeric CcO so generated is no more stable than the original complex and easily dissociates into monomers if the bile salt is removed. The dimerization process is dependent upon a full complement of subunits; e.g., if subunits VIa and VIb are removed, the resulting monomeric CcO will not reassociate upon the addition of sodium cholate. These results support four important consequences: (1) dissociation of dimeric CcO into monomers is reversible; (2) stable dimers can be produced under solution conditions; (3) dimers can be stabilized even at relatively high pH and low enzyme concentration; and (4) subunits VIa and VIb are required for dimerization.

Animals↗
PubMed2004

Modulation with acetonitrile of the dynamics of guest binding to the two distinct binding sites of cholate aggregates.

Bile salt aggregates are supramolecular systems containing two different binding sites. The effect of the addition of acetonitrile on the specificity and dynamics of guest binding to the two binding sites of cholate aggregates was studied. The protection of guests included in the aggregate from interaction with ions in the aqueous phase was evaluated from quenching of the singlet and triplet excited states of guest molecules bound to the cholate aggregates. The dynamics of guest binding to the primary and secondary binding sites of the cholate aggregates were determined at increasing acetonitrile mole fractions. The structure of the aggregates was not significantly altered provided the cholate concentrations were higher than 20 mM and the acetonitrile mole fraction did not exceed 0.033 (9.1% v/v). These results show that acetonitrile can be used to modulate the solubility of guests in the aggregates and to manipulate the residence time of guests in the primary and secondary binding sites.

Acetonitriles↗
PubMed2003

Antifolate resistance associated with loss of MRP1 expression and function in Chinese hamster ovary cells with markedly impaired export of folate and cholate.

Export of folates from a Chinese hamster ovary PyrR100 cell line is markedly impaired, resulting in expansion of cellular folate pools and high-level antifolate resistance. We now report that MRP1 expression is absent in PyrR100 cells along with a marked decrease in MRP5 expression with 3-fold cross-resistance to thiopurines. PyrR100 and wild-type cells had comparable low levels of MRP2 expression; both lacked the breast cancer resistance protein. PyrR100 cells showed a 4-fold decrease in cholate (an MRP substrate) efflux with a 6-fold increase in cellular cholate accumulation compared with wild-type cells. Prostaglandin A1 increased cholate accumulation in wild-type cells to levels comparable with PyrR100 cells. Calcein (an MRP1 substrate) fluorescence increased 5-fold in PyrR100 cells; probenecid increased the intracellular calcein level in wild-type cells to that of PyrR100 cells. Consistent with the loss of MRP1 expression, PyrR100 cells showed modest collateral sensitivity to cholate, etoposide, doxorubicin, and vincristine. Transfection of MRP5 into PyrR100 cells did not alter sensitivity to pyrimethamine or MTX but restored sensitivity to mercaptopurines, indicating that decreased MRP5 expression did not play a role in antifolate resistance. Hence, although MRP-mediated anticancer drug resistance has been associated with gain of function (i.e., overexpression), this is the first report that loss of MRP1 efflux function can expand intracellular folate pools to result in acquired antifolate resistance. The data also suggest that MRP1, and possibly other MRPs that transport folates, can play a role in the maintenance of cellular folate homeostasis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

The Bifidobacterium longum NCIMB 702259T ctr gene codes for a novel cholate transporter.

Preexposure of Bifidobacterium longum NCIMB 702259T to cholate caused increased resistance to cholate, chloramphenicol, and erythromycin. The B. longum ctr gene, encoding a cholate efflux transporter, was transformed into the efflux-negative mutant Escherichia coli KAM3, conferring resistance to bile salts and other antimicrobial compounds and causing the efflux of [14C]cholate.

Amino Acid Sequence↗
PubMedDate not supplied

Feedback regulation of bile acid synthesis in the rat by dietary vs. intravenous cholate or taurocholate.

The regulation of bile acid synthesis was studied (i) in intact or colectomized rats receiving cholate or taurocholate as a dietary supplement and (ii) in experiments using chow-fed animals with a graded intravenous or intraduodenal taurocholate infusion. After the 2-week diet period a bile fistula was established and rates of taurocholate, tauromuricholate and taurochenodeoxycholate secretion were quantitated by high-performance liquid chromatography. During the infusion experiments taurocholate production was calculated from the difference in specific activity of [14C]taurocholate between infusate and bile, whereas tauromuricholate and taurochenodeoxycholate synthesis was derived directly from their secretion rates after pool depletion. Both the 0.5% cholate and taurocholate diet suppressed tauromuricholate and taurochenodeoxycholate secretion nearly totally, but only cholate led to a prolonged inhibition taurocholate synthesis. The diets stimulated total bile acid secretion and expanded the total bile acid pool size 2- to 3-fold, but they also prompted a dramatic increase in the biliary secretion of taurodeoxycholate. In contrast, colectomized animals did not secrete taurodeoxycholate following the cholate diet and, despite a comparable increase in bile acid pool size, tauromuricholate and taurochenodeoxycholate secretion was inhibited to a lesser extent. In addition, the rate of bile acid secretion and synthesis was significantly enhanced when compared to that of intact rats. To determine whether taurocholate affected bile acid synthesis directly, the bile acid was infused intravenously or intraduodenally at varying rates up to 300 mumoles per kg per hr for 54 hr, i.e. a rate exceeding normal total bile acid secretion in these acute bile fistula animals nearly 3-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of sodium cholate on experimental carcinogenesis and cell proliferation in an excluded colonic segment.

Bile salts appear to be important promoters of colon carcinogenesis. This study was designed to assess the importance of the fecal stream in cholic acid-induced colon tumor promotion. Male Sprague-Dawley rats underwent transverse colostomy after induction with dimethylhydrazine (DMH) and the excluded distal colon was irrigated with saline or sodium cholate (23 microM) 5 times per week until sacrifice. Controls initially injected with saline were similarly treated. All surviving animals were sacrificed at 28 weeks after the last DMH injection. Five animals from each group were randomly chosen to assess tritiated thymidine labeling and distribution by autoradiography in normal appearing colon mucosa of irrigated bowel. Cholate irrigation failed to increase tumor yield or modify the proportion of adenomas and adenocarcinomas in this model. Paradoxically, fewer tumors per affected rat were noted with sodium cholate irrigation. Cholate irrigation also failed to affect crypt cellularity, thymidine labeling indices, and labeling distribution in DMH-treated rats and controls. An effect of DMH was seen, however, with an increase in thymidine labeling index and increased labeling in the top half of the crypt in all DMH-treated groups. This study suggests that tumor promotion with primary bile salts is not a direct affect and may result from further bile salt metabolism within the fecal stream. DMH-induced changes in cell proliferation were reproduced with this model. Use of an excluded colon segment to assess the effect of suspected tumor promoters on carcinogenesis or colon mucosal cell proliferation is feasible and may be a useful model for future studies.

Animals↗
PubMed1980

Further characterization of the lipid-depleted bovine rhodopsin obtained by cholate-ammonium sulfate fractionation.

The rhodopsin preparation obtained by the method of ammonium sulfate fractionation contained 3-6 mol phospholipid and about 18 mol cholate per mol rhodopsin. The purified rhodopsin had 74% helical structure and showed a visible CD spectrum different from that of rhodopsin in the membrane. The rhodopsin was stable below but denatured gradually above 20 degrees C. The lifetime of metarhodopsin I was long in this preparation. Regeneration capacity was low and only 30% of the original rhodopsin was regenerable by addition of 11-cis-retinal after bleaching. 50 mol of phosphatidylcholine were maximally bound to 1 mol rhodopsin when the purified rhodopsin was mixed with phosphatidylcholine in 0.5% cholate. The rhodopsin recombined with lipid has properties similar to those of the original rhodopsin in the membrane. Exchange of cholate for other detergents was easily performed by dialysis. The rhodopsin preparation in which cholate was exchanged for digitonin gave almost the same CD, thermal stability and regenerability as those of native rhodopsin in the membrane but metarhodopsin I still retained its long lifetime.

Ammonium Sulfate↗
PubMed1985

Further characterization of 3'-isothiocyanatobenzamido[3H]cholate binding to hepatocytes. Correlation with bile acid transport inhibition and protection by substrates and inhibitors.

Binding of 3'-isothiocyanatobenzamido[3H]cholate ([3H]IBCA) to hepatocytes correlates to its efficacy in inhibiting cholate uptake in isolated hepatocytes. The correlation is linear up to 20 microM [3H]IBCA. Labeling of polypeptides is proportional to the degree of inhibition particularly for a protein of molecular weight 50 000. Transported substrates, competitive and non-competitive inhibitors of cholate transport protect against IBCA inhibition. Additionally binding of [3H]IBCA to isolated plasma membranes is prevented by the same substrates and inhibitors of the cholate transport system. The prevention is achieved by taurocholate, iopodate, iodipamide, furosemide, BSP, cyclosporin A, and somatostatin analogs. Protection is correlated to the degree of transport inhibition and depends on the hydrophobicity of the compounds. Other inhibitors known to destroy the driving forces such as valinomycin do not protect membrane proteins against coupling with IBCA. Silybin, which preferentially alters membrane fluidity, has little effect on the labeling. The above results give further evidence that IBCA, when applied in concentrations below 20 microM, is a suitable label for the hepatocellular bile salt transporter.

Affinity Labels↗
PubMed1986

Cholate-soluble and -insoluble iron binding components of rabbit duodenal brush-border membrane. Relevance to Fe2+ uptake by brush-border membrane vesicles.

Fe2+ uptake by brush-border membrane vesicles from rabbit duodenum has been investigated and found to show similar qualitative properties to those previously demonstrated with mouse proximal intestine brush-border membrane vesicles (Simpson, R.J. and Peters, T.J. (1986) Biochim. Biophys. Acta 856, 109-114). In particular, a relatively low affinity (Km(app) approx. 83 microM), NaCl and pH sensitive transport component is present. The disruption of 59Fe2+-laden vesicles with sodium cholate, followed by gel filtration or centrifugal analysis reveals that cholate insoluble material (Mr greater than 10(6)) is the major destination for 59Fe2+ taken up by intact vesicles. Analysis of cholate extracts for Fe2+ binding ability reveals a single high-capacity (49.8 +/- 15.6 nmol/mg vesicle protein (S.E., n = 3)), high-affinity (Kd(app) less than 5 microM) binding component with an Mr equivalent to approx. 10(4) on gel filtration in the presence of cholate. This binding component is extracted into chloroform/methanol (2:1, v/v) is relatively heat and protease resistant and thus appears to be a lipid.

Animals↗
PubMed1989

Comparison of phosphatidylethanolamine and phosphatidylcholine vesicles produced by treating cholate-phospholipid micelles with cholestyramine.

We have previously reported the preparation and characterization of unilamellar phosphatidylcholine vesicles from cholate-phospholipid micelles treated with the bile-salt sequestrant cholestyramine (Ventimiglia, J.B., Levesque, M.C., and Chang, T.Y. (1986) Anal. Biochem. 157, 323-330). We now describe a slightly modified procedure for forming unilamellar vesicles consisting of phosphatidylethanolamine, and the characterization of the resultant vesicles by gel exclusion chromatography. In contrast to phosphatidylcholine vesicles, the formation of phosphatidylethanolamine vesicles is highly pH dependent; pH 9.2 is superior to pH 8.1 or pH 7.1. Via the dialysis step, the final pH of the vesicles could be altered to be at 8.1 or at 7.1, although decreasing the pH from 9.2 resulted in the loss of approx. 20% of the total lipid as large aggregates. Residual cholate was still present in the resultant vesicles after cholestyramine treatment; the low levels of cholate, removable by dialysis, was found to stabilize the phosphatidylethanolamine vesicles formed at pH 8.1. These results suggest that the majority of the amino groups of the phosphatidylethanolamine molecules should either be in the deprotonated form, or be neutralized and/or restricted by the anionic cholate monomers in order to facilitate the vesicle formation. Phosphatidylethanolamine vesicles were found to be much more permeable to small ions than phosphatidylcholine vesicles. The incorporation of phosphatidylserine, but not phosphatidylinositol, into the phosphatidylethanolamine vesicles at 10% resulted in decreased permeability of the bilayer against the cobalt ion influx, suggesting cooperative and complementary packing of phosphatidylethanolamine and phosphatidylserine molecules within the bilayer.

Cholestyramine Resin↗
PubMed1978

Bile acid pool changes and regulation of cholate synthesis in experimental diabetes.

The effect of alloxan-diabetes and insulin treatment in bile acid pool size and composition, bile acid secretion and cholic acid synthesis was investigated in the rat. The size of the cholate pool was significantly increased 4 days after diabetes induction. It reached a constant size three times that of control animals after 2 weeks of diabetes. Changes in bile acid pool size and secretion were directly dependent of the insulin deficiency state since they were reversed by insulin treatment and were not influenced by the caloric intake of the animal nor the pharmacologic effect of alloxan. Biliary cholate secretion was also 3-fold increased in diabetic rats and it accounted for more than 80% of the total bile acids compared to 60% in the control group. The calculated daily rate of cholate synthesis was increased in diabetic rats and the circadian rhythm of cholate synthesis was abolished in this condition. Therefore, it was shown that the negative feedback mechanism that regulates bile acid snythesis was deleted in diabetes. This mechanism was partially restored after 2 weeks of insulin treatment. These studies demonstrated that bile acid metabolism was profoundly changed in alloxan-diabetic rats and suggested that insulin may play an important role in the regulation of bile acid snythesis and intestinal absorption.

Animals↗
PubMed1991

Cholate separates the catalytic and malonyl-CoA-binding components of carnitine palmitoyltransferase from liver outer mitochondrial membranes.

Sodium cholate was used as an anionic detergent to discriminate the two components of liver overt carnitine palmitoyltransferase (CPT1); namely a catalytic entity and a regulatory component that bound malonyl-CoA. Cholate solubilized approx. 40% of the malonyl-CoA binding entity from mitochondrial outer membranes without appreciable solubilization of CPT1 activity. Cholate did not interfere with binding of [14C]malonyl-CoA to outer membranes or to crude total mitochondrial membrane fractions. By contrast, the non-ionic detergent Tween-20 was ineffective in solubilizing the malonyl-CoA binding entity and also substantially interfered with the binding of [14C]malonyl-CoA. Both detergents appeared to cause total disengagement of the malonyl-CoA binding entity from the catalytic entity of CPT1 only when some inner membrane material was present. 'Reconstitution' experiments were performed in which a malonyl-CoA sensitivity conferring factor in cholate extracts from outer membranes was associated with CPT derived from inner membranes (CPT2). The IC50 for inhibition of CPT2 by malonyl-CoA in this artificial system was similar to that observed with CPT1 in situ in outer membranes. Extracts containing malonyl-CoA sensitivity conferring factor derived from outer membranes of fed or 48 h fasted rats were associated with CPT2 derived from fed rats. The outer membrane extracts from fasted animals conferred a lower maximum responsiveness to malonyl-CoA, but appeared to have a higher affinity for CPT2 than the extracts from fed rats. These results suggest that physiological state can alter the intrinsic properties of the malonyl-CoA sensitivity confering factor.

Animals↗
PubMed1987

Cholesterol metabolism and esterases in four strains of rats with differential cholesterolemic responses to a high-cholesterol, high-cholate diet.

The increase in serum cholesterol after feeding a diet containing 2% (w/w) of cholesterol and 0.5% of cholate for 13 days was 200 and 800% in two hypo- and two hyper-responsive inbred strains of rats, respectively. While remaining on the high-cholesterol, high-cholate diet for longer periods, the level of serum cholesterol dropped in the hyper-responsive strains, and after 8 weeks on the diet one hyper-responsive strain had similar serum cholesterol concentrations as the two hypo-responsive strains. The feeding of a semipurified diet, containing 1% (w/w) of cholesterol and 20% of fat, did not discriminate between the two hypo- and hyper-responsive strains with respect to the response of serum cholesterol. The activities in plasma of the indicators for liver function, aspartate amino transferase and alkaline phosphatase, were significantly increased in all strains after feeding the high-cholesterol, high-cholate diet. Only alkaline phosphatase was increased by the semipurified diet. Evidence is presented that in the four inbred strains of rats the differential cholesterolemic response to the high-cholesterol, high-cholate diet is not related to the baseline serum lipoprotein profile, liver cholesterol accumulation, fecal bile acid excretion, and the total activities and patterns of esterases in serum, liver and small intestine.

Animals↗
PubMed2003

Use of cholate derivatives with submicellar concentration for controlling selectivity of proteins in hydrophobic interaction chromatography.

Hydrophobic interaction chromatography (HIC) of proteins using a phenyl column has been performed in the presence of various surfactants with micellar and submicellar concentration ranges. Most surfactants were effective for a decrease in the retention of proteins in both concentration ranges. However, the use of anionic cholate derivatives increased the retention of the proteins with high isoelectric point, such as lysozyme, cytochrome c, and trypsin, in submicellar concentration range, and then decreased it above the critical micellar concentration, while the retention of the other proteins was monotonously decreased. The results of frontal chromatographic analysis of the surfactant and capillary electrophoresis for the proteins in the presence of surfactant show that in the submicellar concentration range, cholate derivatives allowed to be adsorbed on the stationary phase, while they exhibited no interactions with the proteins. Thus, it appeared that the increase in the retention of basic proteins was due to the electrostatic attraction between the proteins and cholate-modified stationary phase. We have applied the unique property of cholate to the separation of ovalbumin and lysozyme in egg white sample using hydrophobic chromatography.

Cholic Acid↗
PubMed1967

The influence of conjugation of cholic acid on its uptake and secretion: hepatic extraction of taurocholate and cholate in the dog.

1. Sodium taurocholate or cholate was administered systemically at a constant rate of about 2.9 mumole/min.kg body wt. to anaesthetized dogs in which the common bile duct had been cannulated. In steady-state conditions blood was sampled from systemic and hepatic veins and the fraction of bile salt removed in a single passage through the liver was determined. Total hepatic blood flow was estimated by application of the Fick principle.2. The hepatic extraction fraction for synthetic taurocholate in ten experiments was 92%+/-5% (S.D.) over the blood flow range encountered (1.1-2.8 ml./min.g liver). The extraction of cholate extensively conjugated in the liver before excretion into bile was 79%+/-8% (S.D.) (twenty-one observations, thirteen experiments). In circumstances of similar hepatic blood flow the extraction of cholate transferred to bile in the free form (after acute taurine depletion) was significantly less than that of either synthetic taurocholate or cholate which could be actively conjugated before excretion. These results, which are discussed and criticized, support previous work on the advantage of conjugation in the transfer of cholic acid from blood to bile.3. The hepatic clearance of bile salt decreases with increasing administration rate, but the values obtained may be influenced by changes in hepatic blood flow. With regard to taurocholate an increase in total hepatic flow was observed when its administration rate exceeded about 5 mumole/min.kg body wt.4. The secretory maximum for glycocholate, a bile salt not normally found in dog bile, was of the same order as that for taurocholate.

Animals↗
PubMed2000

Effects of nonpolar mutations in each of the seven Bacillus subtilis mrp genes suggest complex interactions among the gene products in support of Na(+) and alkali but not cholate resistance.

The Bacillus subtilis mrp (multiple resistance and pH) operon supports Na(+) and alkali resistance via an Na(+)/H(+) antiport, as well as cholate efflux and resistance. Among the individual mutants with nonpolar mutations in each of the seven mrp genes, only the mrpF mutant exhibited cholate sensitivity and a cholate efflux defect that were complemented by expression of the deleted gene in trans. Expression of mrpF in the mrp null (VKN1) strain also restored cholate transport and increased Na(+) efflux, indicating that MrpF does not require even low levels of other mrp gene expression for its own function. In contrast to MrpF, MrpA function had earlier seemed to depend upon at least modest expression of other mrp genes, i.e., mrpA restored Na(+) resistance and efflux to strain VK6 (a polar mrpA mutant which expresses low levels of mrpB to -G) but not to the null strain VKN1. In a wild-type background, each nonpolar mutation in individual mrp genes caused profound Na(+) sensitivity at both pH 7.0 and 8.3. The mrpA and mrpD mutants were particularly sensitive to alkaline pH even without added Na(+). While transport assays in membrane vesicles from selected strains indicated that MrpA-dependent antiport can occur by a secondary, proton motive force-dependent mechanism, the requirement for multiple mrp gene products suggests that there are features of energization, function, or stabilization that differ from typical secondary membrane transporters. Northern analyses indicated regulatory relationships among mrp genes as well. All the mrp mutants, especially the mrpA, -B, -D, -E, and -G mutants, had elevated levels of mrp RNA relative to the wild type. Expression of an upstream gene, maeN, that encodes an Na(+)/malate symporter, was coordinately regulated with mrp, although it is not part of the operon.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

Effect of sodium cholate on the phase transition temperature of dipalmitoyl phosphatidylcholine.

On treatment with sodium cholate, the phase transition temperature (Tc) of multilamellar liposomes derived from dipalmitoyl phosphatidylcholine (DPPC) progressively decreased with increasing cholate: lipid-P molar ratio. A molar ratio of 4.5 caused a one degree depression in Tc. The unilamellar cholate vesicles of DPPC exhibited the same Tc as that of the multilamellar ones. The formation of unilamellar vesicles from the multilamellar ones by cholate treatment was investigated by electron microscopy.

Cholic Acid↗
PubMed1988

Effects of ammonium acetate and sodium cholate on N-methyl-N'-nitro-N-nitrosoguanidine-induced colon carcinogenesis of rats.

This study was conducted to determine the effects of ammonium acetate alone or in combination with sodium cholate upon N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced colon carcinogenesis in rats. Ammonia, acetate, and deconjugated bile acids are produced by microbial enzymes in the gastrointestinal lumen. One hundred twenty male Sprague-Dawley rats, weighing 196 +/- 2 g at 8 wk of age, were given four intrarectal doses of MNNG (2 mg/dose) over 2 wk. They were then randomly assigned among four treatment groups, each containing 30 rats. The groups were arranged in a 2 x 2 factorial design and given intrarectal infusions of the agents under study in 0.3 ml of double-distilled water 3 times weekly for 52 wk beginning 4 wk after the initial MNNG treatment. The experimental treatments were: double-distilled water as control; ammonium acetate (24.8 mg of ammonia); sodium cholate (2 mg of cholic acid); and a combination of ammonium acetate and sodium cholate. Ammonium acetate treatment increased the number of rats with fecal blood 4-fold after 56 wk, and this was associated with a higher incidence of adenocarcinomas with a polypoid morphology. The incidence and total number of carcinomas in situ (high grade dysplasia) increased with ammonium acetate treatment. Ammonium acetate increased the total number of adenocarcinomas. Sodium cholate had no significant main effects on the incidence or morphology of colon lesions. The data support the conclusion that ammonium acetate treatment acted as a promoting agent in MNNG-induced colon carcinogenesis.

Acetates↗