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At least 199 records · Page 11Linked to original sources
PubMed1984

Dehydroxylation of cholic acid at C12 and epimerization at C5 and C7 by Bacteroides species.

Freshly isolated cultures (2060) of human intestinal bacteria of the predominant flora, among them 1029 strains of saccharolytic Bacteroides species, were tested for cholic acid transformation. Eight Bacteroides strains reduced cholate to chenodeoxycholate, while 73 strains dehydroxylated at C7, producing deoxycholate. Concurrent oxidation of hydroxyl groups, mainly at C7, was seen with many strains. No strain was able to dehydroxylate simultaneously at C7 and C12. One isolate, identified as a mixed culture of Bacteroides fragilis and B. uniformis, epimerized cholic acid at C5 and simultaneously epimerized, oxidized and dehydroxylated at C7. The following transformation products were identified: 3 alpha,7 alpha,12 alpha-trihydroxy-5 alpha-cholanoic acid, 3 alpha,7 beta,12 alpha-trihydroxy-5 beta-cholanoic acid (ursocholic acid), 3 alpha,12 alpha-dihydroxy-7-keto-5 beta-cholanoic acid, 3 alpha,12 alpha-dihydroxy-5 alpha-cholanoic acid and a 3 alpha,12 alpha-dihydroxy-5 alpha-cholenoic acid. Dehydroxylating and epimerizing abilities were detected when fresh isolates were tested first for cholate transformation. They were no longer recognizable after some serial transfers. Dehydroxylation at C12 of cholate could not be demonstrated with mixed fecal cultures. The possible intermediate, however, 3 alpha,7 alpha-dihydroxy-5 beta-chol-11-enoate, was abundantly hydrogenated by stool suspensions.

Bacteroides↗
PubMed1992

Role of endocardial endothelium in the positive inotropic effect of cholic acid in isolated myocardium.

In isolated feline right ventricular papillary muscles, with intact or damaged (exposure to dry air for 30 s) endocardium, the effects of cholic acid were studied. At 35 degrees C and a [Ca2+] of 1.25 mM, isometric twitches and the maximal unloaded velocity of shortening (Vmax) were registered. Endocardial endothelium (EE) and myocardial ultrastructure were evaluated on scanning and transmission electron microscopy. In muscles with intact EE, low concentrations of cholic acid (3 x 10(-9) to 3 x 10(-7) M) or short incubation (30 min) with 3 x 10(-8) M induced a mild positive inotropic response, manifested as an increased peak isometric twitch tension (TT) and shortened twitch duration, without changes in Vmax. This inotropic response was abolished by damaging the EE. It was also absent after the addition of propranolol to muscles with intact EE. Higher concentrations (3 x 10(-6) to 3 x 10(-4) M) or prolonged incubation at 3 x 10(-8) M caused extensive morphologic damage of the EE, without detectable impairment of subjacent myocardium. This was accompanied by a progressive decrease in the TT and further twitch abbreviation, without changes in Vmax, resembling twitches obtained from muscles with experimentally damaged EE. These observations suggest that cholic acid induces an EE-dependent and beta-receptor-mediated positive inotropic effect, while simultaneously causing damage to EE cells.

Animals↗
PubMed2006

Amino functionalized novel cholic acid derivatives induce HIV-1 replication and syncytia formation in T cells.

Synthesis of C-11 azido/amino functionalized cholic acid derivatives has been achieved in excellent yields. Contrary to the previous prediction of analogous compounds to be HIV-1 protease inhibitors, in the present study these novel cholic acid derivatives induced host cell fusion during the progress of HIV-1 infection and produced multinucleated giant cells. This is the first report of syncytia induction and enhancement of viral replication in HIV-1 infected T cells by cholic acid derivatives.

CD4-Positive T-Lymphocytes↗
PubMed1988

Increased rate of cholic acid formation from 3 alpha,7 alpha-dihydroxy-5 beta-cholestane in perfused livers from diabetic rats.

The formation of bile acids from 3 alpha,7 alpha-dihydroxy-5 beta-cholestane was comparatively investigated in the perfused livers from normal, streptozotocin-diabetic, and insulin-treated diabetic rats. During the infusion of the sterol substrate, cholic acid accounted for only 11% of the total biliary bile acids in the normal rats, while it increased drastically to 57% in the diabetic rats. This increased proportion of cholic acid tended to be normalized by treatment of the diabetic animals with insulin. These results suggest the possible acceleration of cholic acid formation, involving 12 alpha-hydroxylation of 3 alpha,7 alpha-dihydroxy-5 beta-cholestane or one of its metabolites in an insulin-deficient state in rats.

Animals↗
PubMed1981

The extent of reflux of unconjugated 14C-cholic acid from the liver in subjects with normal liver function.

An improved understanding of bile acid physiology is a prerequisite for the construction of an acceptable model for describing plasma clearance of bile acids. The aim of this study was to determine the extent of reflux unconjugated cholic acid from the liver to the plasma in subjects with normal liver function. The clearance of a bolus injection of unconjugated 14C-cholic acid was studied in four subjects using samples collected simultaneously from a peripheral and a hepatic vein. Hepatic extraction ratios calculated directly from the data were found to be essentially constant during the 20 min following injection, with average values of 0.60-0.72. This indicates that reflux did not occur significantly in the subjects investigated. These results are interpreted as favouring a model in which exchange of unconjugated 14C-cholic acid occurs between the plasma and a peripheral compartment with final removal from the plasma to the liver.

Carbon Radioisotopes↗
PubMed1993

Activation of a peroxisome-proliferating catabolite of cholic acid to its CoA ester.

We have shown that a microbial cholic acid catabolite (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo- 1H-cyclopenta[f]quinolin-7 beta-yl)valeric acid (DCQVA), is a potent peroxisome proliferator. In this paper a possible key stage in DCQVA metabolism, the activation of DCQVA to its CoA ester, has been investigated in rat liver microsomes and particulate fractions. The microsomal reaction was dependent on CoA, ATP, DCQVA (0.2-1 mM) and protein content. The reaction was decreased by storage at 4 degrees C, preincubation of microsomes at 37 degrees C for 5 min, or inclusion of Triton X-100 in the reaction mixture. Such treatments also enhanced generation of long-chain fatty acyl-CoAs, as determined by h.p.l.c. analysis. The same effect was caused by exposing the microsomes to phospholipase A2, suggesting that endogenous fatty acids may compete with DCQVA for esterification with CoA. Subcellular fractionation of rat liver demonstrated that the activity of DCQVA-CoA synthesis was localized predominantly in the microsomal fraction, in contrast to long-chain fatty acyl-CoA synthetase, which was distributed among all particulate fractions. Administration of clofibrate of rats did not affect the distribution of DCQVA-CoA synthesis activity. In contrast to a 2-fold induction of long-chain fatty acyl-CoA synthetase by clofibrate treatment, the activity of DCQVA-CoA synthesis in the microsomal fraction decreased by 80%. These results suggest that DCQVA is activated by an enzyme distinct from long-chain fatty acyl-CoA synthetase. The resulting perturbation of fatty acid metabolism may be involved in the mechanism whereby DCQVA causes peroxisome proliferation.

Acyl Coenzyme A↗
PubMedDate not supplied

Hepatobiliary delivery of polyaminopolycarboxylate chelates: synthesis and characterization of a cholic acid conjugate of EDTA and biodistribution and imaging studies with its indium-111 chelate.

A conjugate in which the steroid nucleus of cholic acid was linked to EDTA via an 11-atom spacer was obtained by reacting the succinimidyl ester of cholic acid with the amine formed by reaction of a benzyl isothiocyanate derivative of EDTA with N-(tert-butoxycarbonyl)ethylenediamine and subsequent deprotection. Potentiometric titration studies with model complexes showed that the EDTA moiety retained the ability to form 1:1 chelates of high thermodynamic stability, although formation constants were some 3-4 log K units lower for complexes of the conjugate than for the analogous chelates with underivatized EDTA. A complex formed between the cholic acid-EDTA conjugate and 111InIII was clearly rapidly into the liver when injected iv into mice, with subsequent excretion from the liver into the gastrointestinal tract being complete within 1 h of injection. Radioscintigraphic imaging studies conducted in a rabbit given the 111In-labeled conjugate also showed early liver uptake followed by rapid clearance from the liver into the intestine, with good visualization of the gallbladder in images obtained at 20-25 min postinjection. It is concluded that conjugation to cholic acid provides a useful means for the hepatobiliary delivery of EDTA chelates that otherwise exhibit predominantly extracellular distribution and renal clearance.

Animals↗
PubMed2005

[The protective effect of cholic acid on an in vitro injury model of ischemia-reperfusion in cerebral microvascular endothelial cells].

OBJECTIVE: To establish an in vitro injury model of ischemia-reperfusion in cerebral microvascular endothelial cells of rats and observe the protective effect of cholic acid. METHOD: Cultured rat microvascular endothelial cells were subjected to the oxygen-glucose deprivation (OGD) (Krebs solution) and recovery of oxygen-glucose, which simulated in vitro ischemia and reperfusion injury, and treated with cholic acid. The A value was measured with MIT chromatometry. RESULT: Cultured cells were impaired after OGD for 4 hours and recovery of oxygen-glucose for 12 hours, the A value of the cells treated with cholic acid was significantly higher than that of the cells without treatment (P < 0.01). CONCLUSION: Cholic acid could obviously protect rat cerebral microvascular endothelial cells from injury induced by an in vitro ischemia-reperfusion.

Animals↗
PubMed1992

Effect of basic cholane derivatives on intestinal cholic acid metabolism: in vitro and in vivo activity.

A representative series of hydroxy-5 beta-cholanyl-24-amines were tested both in vitro and in vivo with respect to their activity against the intestinal bacteria responsible for bile acid metabolism. For the in vitro studies, radiolabeled [14C]cholic acid was incubated with human stools both in aerobic and anaerobic conditions in the presence of the title compounds at a dose of 10 micrograms/mL, and the biotransformation of cholic acid into radiolabeled deoxycholic acid and other metabolites was followed by TLC-radiochromatography. Of the compounds studied, 3 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-N-methylamine showed the highest activity. This compound was used for the in vivo studies and was shown to inhibit the formation of endogenous secondary bile acids when chronically administered to rats at a dose of 60 micrograms/day for 15 days. The treated rats showed an increased ratio of taurocholic acid (primary bile acid) to taurodeoxycholic acid (secondary bile acid) in bile, a fact further suggesting a potent antibacterial activity of the compound toward bacteria responsible for bile acid metabolism.

Aerobiosis↗
PubMed2000

Preparation of a protected triamino analogue of cholic acid and sequential incorporation of amino acids in solution and on a solid support.

We have prepared a triamine derivative of cholic acid with protecting groups on the amines that allow sequential amide formation. The triamine was formed from 3 alpha,7 alpha, 12 alpha-trihydroxycholan-24-ol with good stereoselectivity. Sequential removal of the amine protecting groups and amide formation was achieved in high-yielding steps and was performed in solution and on a solid support.

Amides↗
PubMed1990

Biological properties of the 2-fluoro-beta-alanine conjugates of cholic acid and chenodeoxycholic acid in the isolated perfused rat liver.

The isolated perfused rat liver was used to examine the hepatic extraction, biliary secretion and effect on bile flow of the 2-fluoro-beta-alanine conjugates of cholic acid and chenodeoxycholic acid. The naturally occurring taurine and glycine conjugates of these bile acids were used for comparisons. The 2-fluoro-beta-alanine conjugates were extracted by the liver to a similar extent as the taurine and glycine conjugates. The biliary secretion rate and increase in bile flow were similar for all the cholic acid conjugates. On the other hand, the maximal biliary secretion rate of the 2-fluoro-beta-alanine conjugate of chenodeoxycholate was similar to that of the glycochenodeoxycholate, but 47% lower than that of taurochenodeoxycholate. In addition, the 2-fluoro-beta-alanine conjugate of chenodeoxycholate produced a decrease in bile flow that was comparable to that observed with the glycochenodeoxycholate (54% vs. 74%), but which was greater than that produced by the taurochenodeoxycholate (12%). In summary, these data demonstrate that the biological properties of the 2-fluoro-beta-alanine conjugates of cholic acid and chenodeoxycholic acid are not markedly different from those of the naturally occurring taurine and glycine conjugates. These data also suggest that the amino acid moiety can influence the biliary secretion and cholestatic properties of chenodeoxycholic acid conjugates.

Alanine↗
PubMed1996

Growth features of aberrant crypt foci that resist modulation by cholic acid.

Previously, we demonstrated that feeding rats a diet containing 0.2% cholic acid (CHA-diet) resulted in the elimination or remodelling of a number of aberrant crypt foci (ACF) in their primal stages (1-3 crypts/focus). The present investigation was conducted to determine if ACF with advanced growth features will respond differently than their primal counterparts to the CHA-diet. Sprague-Dawley male rats were injected with azoxymethane (20 mg/ kg) and were maintained on a control diet for 21 weeks. At week 21, three rats were killed and their colons were assessed for ACE. The remaining animals were randomly divided into two groups, which were fed a control diet or a CHA-diet respectively, After 3 weeks of feeding, the rats (n = 5) were killed and their colons were assessed for the number, size (area occupied by each focus) and crypt multiplicity (number of crypts/focus). The CHA-diet resulted in a significant (P </= 0.05) reduction in the number of ACF with 1-2 crypt multiplicity. When compared to the control group, the CHA group ACF with 1-2 crypts/focus were reduced by 70%; with 3-4 crypts/focus, a 48% reduction; and with >4 crypts/focus, a 50.4% reduction. Treatment with CHA resulted in a marked reduction in the population of ACF with 1-2 or 3-4 crypt multiplicity with area >5-1Ox10(-2) mm2. These findings demonstrate that ACF with advanced growth features are phenotypically different from their primal counterparts in resisting the responses elicited by the CHA-diet even at a late time point, and that morphological heterogeneity among ACF may represent different biological states.

Analysis of Variance↗
PubMed1999

Methylprednisolone administration in primary biliary cirrhosis increases cholic acid turnover, synthesis, and deoxycholate concentration in bile.

As immunosuppressive agents, corticosteroids may be considered an appropriate treatment for primary biliary cirrhosis, even if bone loss and other side effects may occur. We studied biliary lipid metabolism in 10 nonicteric patients, with histologically proven primary biliary cirrhosis (stage I-IV). We administered methylprednisolone (24 mg daily) for 30 days to ascertain its effects on biliary lipid metabolism, which are largely still unknown. All patients underwent a 30-day drug-washout period before entering the trial. The following parameters were studied before and after methylprednisolone treatment: serum biochemistry; cholic acid pool size, kinetics and synthesis; biliary lipid secretion; biliary bile acid pattern; biliary lipid molar percentage; and cholesterol saturation index. Methylprednisolone induced a statistically significant (Wilcoxon rank test) increase in cholic acid turnover (from 0.26+/-0.04 to 0.50+/-0.05 K/day, P = 0.005) and synthesis (from 0.42+/-0.12 to 0.78+/-0.11 mmol/day, P = 0.04), and in bile deoxycholic acid molar percentage (from 19.4+/-2.7 to 30.6+/-4.4% molar, P = 0.01). On the other hand, a significant decrease in biliary cholesterol molar percentage (from 7.9+/-0.7 to 6.4+/-0.5% molar, P = 0.005), cholesterol saturation index (from 1.11+/-0.11 to 0.95+/-0.07, P = 0.05), and biliary cholesterol secretion (from 64.7+/-5.4 to 53.0+/-4.5 micromol/hr, P = 0.005) was observed. These findings show that short-term administration of methylprednisolone in patients with primary biliary cirrhosis does not induce expansion of the cholic acid pool but increases cholic acid synthesis and turnover, as well as intestinal production of deoxycholic acid. If long-term treatment is considered, the beneficial immunosuppressive effects of corticosteroids have to be weighed against the hepatotoxic properties of deoxycholic acid.

Adult↗
PubMed2001

Transmembrane ion channels constructed of cholic acid derivatives.

A new class of supramolecular transmembrane ion channels was prepared by linking two amphiphilic cholic acid methyl ethers through biscarbamate bonds to afford bis(7,12-dimethyl-24-carboxy-3-cholanyl)-N,N'-xylylene dicarbamate 2 and bis[7,12-dimethyl-24-(N,N,N-trimethylethanaminium-2-carboxylate)-3-cholanyl]-N,N'-xylylene dicarbamate dichloride 3. When incorporated into a planar bilayer membrane, both compounds showed stable (lasting 10 ms to 10 s) single ion channel currents. Only limited numbers of relatively small conductances were characterized for these channels (5-20 pS for 2 and 5-10 pS for 3, 10 and 17 pS for 2, and 9 pS for 3 in particular). Both channels were cation selective, and permeability ratios of potassium cation to chloride anion were 17 and 7.9 for 2 and 3, respectively, reflecting the difference in ionic species of the headgroup. Both channels 2 and 3 showed significant potassium selectivity over sodium by a factor of 3.1 and 3.2, respectively. No Li(+) currents were observed for 2, showing sharp discrimination between Na(+) or K(+).

Carboxylic Acids↗
PubMed1996

Regulation of the last two enzymatic reactions in cholesterol biosynthesis in rats: effects of BM 15.766, cholesterol, cholic acid, lovastatin, and their combinations.

The Smith-Lemli-Opitz syndrome is a common inherited birth disorder caused by markedly reduced 7-dehydrocholesterol delta 7-reductase activity, the final enzyme in the cholesterol biosynthetic pathway. BM 15.766 (4-[2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) inhibits 7-dehydrocholesterol delta 7-reductase activity, reduces plasma cholesterol levels, and increases 7-dehydrocholesterol levels to reproduce the biochemical abnormalities of the syndrome in rats. Cholesterol, cholic acid, and lovastatin, alone or in combinations, were fed to rats given BM 15.766, and hepatic activities of the last two enzymes in the cholesterol biosynthetic pathway, lathosterol 5-dehydrogenase and 7-dehydrocholesterol delta 7-reductase, were measured. After feeding BM 15.766, hepatic 7-dehydrocholesterol delta 7-reductase activity decreased by 77% while lathosterol 5-dehydrogenase activity tended to increase, so that the ratio of 5-dehydrogenase to delta 7-reductase activities increased from 0.33 to 2.8. In BM 15.766-fed rats, treatment with cholesterol suppressed both 5-dehydrogenase and delta 7-reductase activities by 76% and 66%, respectively, and decreased the 5-dehydrogenase: delta 7-reductase activities ratio from 2.8 to 2.2. In contrast, treatment with cholic acid and BM 15.766 further inhibited delta 7-reductase activity by 67% without changing significantly the 5-dehydrogenase activity that had increased the ratio to 5.5. Combining BM 15.766 with lovastatin increased 5-dehydrogenase activity fivefold but did not change delta 7-reductase activity, raising the ratio to 14.3. In BM 15.766-treated rats, the first and last two enzymatic reactions in the cholesterol biosynthetic pathway catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lathosterol 5-dehydrogenase, and 7-dehydrocholesterol delta 7-reductase are down-regulated by cholesterol. Thus, only cholesterol and not cholic acid or lovastatin could reduce elevated plasma 7-dehydrocholesterol levels induced by BM 15.766.

Animals↗
PubMed1977

Microbiological degradation of bile acids. The preparation of hexahydroindane derivatives as substrates for studying cholic acid degradation.

Relatively large amounts of 3-(3aalpha-hexahydro-7abeta-methyl-1,5-dioxoindan-4alpha-yl)propionic acid (IIb), which is believed to be one of the intermediates involved in the degradation of cholic acid (I), were needed to identify is further degradation products. A simple method for the preparation of this compound was then investigated. Arthrobacter simplex could degrade-3-oxoandrost-4-ene-17beta-carboxylic acid (IIIa) to 3-(1beta-carboxy-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-4alpha-yl)propionic acid (IVa) in good yield, the structure of which was established by partial synthesis. It was therefore expected that, if a similar degradation by this organism occurred with 17alpha-hydroxy-3-oxoandrost-4-ene-17beta-carboxylic acid (IIIb), which is easily obtained by chemical oxidation of commercially availabe 17alpha-hydroxydeoxycorticosterone, the resulting product, 3-(1beta-carboxy-3aalpha-hexahydro-1alpha-hydroxy-7abeta-methyl-5-oxoindan-4alpha-yl)propionic acid (IVb), could be readily converted chemically into the required dioxocarboxylic acid, (IIb). Exposure of compound (IIIb) to A. simplex produced, as expected, compound (IVb) which was then oxidized with NaBiO3 to give a reasonable yield of compound (IIb).

Arthrobacter↗
PubMed1989

An endogenous colon mitosis inhibitor reduces the increased cell proliferation in colonic epithelium induced by dietary cholic acid and treatment with 1,2-dimethylhydrazine.

We have recently purified and identified a tripeptide (pGlu-His-GlyOH) in mouse intestinal extracts which reversibly inhibits normal colonic epithelial cell renewal in mice. We also found a similar response to a single injection of the peptide during bile-acid-induced hyperproliferation in the colonic epithelium. To investigate the effect of repeated injections of the same dose of the inhibitor under various pathological conditions of the colonic mucosa we either fed mice low-calcium cholic acid diet, treated the animals with a single injection of the colon carcinogen 1,2-dimethylhydrazine (DMH), or gave both treatments. The peptide reduced the mitotic rate and the labelling indices in the colonic epithelium during the first 5 days of feeding the low-calcium cholic acid diet, and the size of the proliferative compartment was reduced. Proliferating cells were found significantly closer to the base of the crypts in the peptide-treated animals. The mitotic rate was also reduced by each of repeated peptide injections during the first 72 h in the DMH-treated animals; the labelling indices at 48 and 72 h only. By feeding DMH-treated animals low-calcium cholic acid diet, similar results were obtained. However, in all carcinogen-treated animals the tripeptide had no effect on the size and localization of the proliferating cells in the colonic crypts.

1,2-Dimethylhydrazine↗