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PubMed1975

Bile alcohol metabolism in man. Conversion of 5beta-cholestane-3alpha, 7alpha,12alpha, 25-tetrol to cholic acid.

To study the role of C25-HYDROXY BILE ALCOHOLS AS PRECURSORS OF CHOlic acid, [G-3-H]5beta-cholestane-3alpha,7alpha12alpha,25-tetrol was administered intravenously to two subjects with cerebrotendinous xanthomatosis (CTX) and two normal individuals. One day after pulse labeling, radioactivity was present in the cholic acid isolated from the bile and feces of the subjects with CTX and the bile of the normal individuals. In the two normal subjects, the sp act decay curves of [G-3-H]-cholic acid were exponential, and no traces of [G-3-H]-5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol were detected. In contrast, appreciable quantities of labeled 5beta-cholestane-3alpha,-7aopha,12alpha,25-tetrol were present in the bile and feces of the CTX subjects. The sp act vs. time curves of fecal [G-3-H]5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol and [G-3-H]-cholic acid showed a precursor-product relationship. Although these results suggest that 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol may be a precursor of cholic acid in man, the possibility that C26-hydroxy intermediates represent the normal pathway can not be excluded.

Alcohols↗

PubMed1996

Validation of [22,23-3H]cholic acid as a stable tracer through conversion to deoxycholic acid in human subjects.

Bile acids labeled with 3H on the sterol nucleus lose a substantial fraction of label during enterohepatic cycling and conversion to secondary bile acids. We tested the isotopic stability of a side-chain 3H label, [22,23-3H]cholic acid in humans. The 3H-labeled compound was administered simultaneously with [24-14C]cholic acid to four healthy volunteers. Duodenal bile was collected daily for 5 days after isotope administration to determine the ratio of 3H/14C in bile acids. Urine was collected to determine loss of radioactivity by this route. Cholic acid and deoxycholic acid were isolated from biliary bile acids by thin-layer chromatography after deconjugation with cholylglycine hydrolase. The ratio of 3H/14C in cholic acid and deoxycholic acid remained constant and identical to that of the administered mixture in all subjects, indicating stability of the 3H label during enterohepatic cycling. Cumulative loss of 3H in urine averaged only 1.2% of administered dose and was identical to loss of 14C (average 1.3%) indicating little if any transfer of 3H from bile acid to body water. Deconjugation of biliary bile acids by alkaline hydrolysis resulted in 15-20% loss of 3H label, consistent with known base-catalyzed exchange of alpha-carbon protons on carboxylic acids. We conclude that [22,23-3H]cholic acid is a biologically stable, and therefore reliable, isotopic tracer of cholic acid in humans during enterohepatic cycling including conversion to deoxycholic acid, provided deconjugation is performed enzymatically. Because the 22,23-3H label can be inserted into most C24 bile acids, it appears the best way to tag 3H-labeled bile acids for metabolic studies.

Adult↗

PubMed1981

The binding of cholic acid to protein in rat serum and liver.

After the intraperitoneal administration of radioactive cholic acid to rats, the binding of the cholic acid to protein was immunologically investigated. The serum and liver cytosol were separately incubated with antiligandin or antialbumin immunoglobulin and then subjected to sucrose density gradient centrifugation. The sedimentation behavior of the radioactivity, endogenous bile acids, glutathione S-transferase activity of ligandin and protein provided evidence that cholic acid is bound to both ligandin and albumin in liver, and mostly to albumin in serum. However, little, if any, cholic acid seems to be bound to protein in bile. These results suggest that ligandin and albumin are the major physiological carriers of bile acid.

Animals↗

PubMed1996

Formation of cholic acid and chenodeoxycholic acid from 7 alpha-hydroxycholesterol and 27-hydroxycholesterol by primary cultures of human hepatocytes.

It has been suggested that chenodeoxycholic acid is preferentially formed by the alternative or 'acidic' pathway of bile acid biosynthesis starting with 27-hydroxylation of cholesterol, while cholic acid is derived from 7 alpha-hydroxycholesterol which initiates the 'neutral' pathway. We have studied bile acid formation from each of these precursors using human hepatocytes cultured in a novel sandwich collagen configuration. Culture supernatants were analyzed using capillary gas chromatography and gas chromatography-mass spectrometry. 27-Hydroxycholesterol and 7 alpha-hydroxycholesterol were both found to be efficiently converted to cholic acid as well as chenodeoxycholic acid. Analysis of acidic intermediates after addition of 7 alpha-hydroxycholesterol to the cultures revealed a significant increase of side-chain oxygenated C24- and C27-steroids with a 3-oxo-7 alpha-hydroxy-delta 4-ring structure. These data indicate that (i) the 'neutral' pathway is connected to the 'acidic' pathway by side-chain oxidation of C27-steroids with a 3-oxo-7 alpha-hydroxy-delta 4-ring structure and that (ii) the relative formation of cholic acid and chenodeoxycholic acid is regulated by metabolic events distal to the initial hydroxylation at either position 7 or position 27 of the cholesterol molecule.

Adult↗

PubMed1976

[The significance of the bacterial steroid degradation for the etiology of large bowel cancer. IV. Deconjugation of glycocholic acid, oxidation, and reduction of cholic acid by saccharolytic Bacteroides species (author's transl)].

A total of 36-38 strains (depending on the test series) of the strictly anaerobic Bacteroides species V. bulgatus, B. fragilis, B. thetaiotamicron, and B. distasonis was tested for the ability of splitting the acide amide linkage of glycocholate and for a further degradation of cholate. We found 23 of 38 strains (60 per cent) to be able to deconjugate glycocholate, but as many as 18 (46 per cent) resulted in an intensive to complete degradation. On the other hand 32 of 36 strains (89 per cent) were able to degrade cholate when cultivated anaerobically. They normally formed 1 transformation product, however, occasionally 2-3. Using the aerobic incubation of resting cells as test system we observed 30 active strains of 37 (81 per cent), which as well produced 1 degradation product generally, but sometimes 2-4 compounds. 3 strains transformed cholate during growth only. Thin layer-, gas chromatography, and combined gas chromatography-mass spectrometry were used for the identification of transformation products. We proved the main degradation product of all active strains to be 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholanoate, by anaerobic cultivation as well as by aerobic incubation of cell suspensions. Deoxycholate (3alpha,12alpha-dihydroxy-5beta-cholanoate), in vivo the main product of cholate transformation, was hitherto found to be formed by 3 strains only as main degradation product, it may probably be a by-product of the degradation with other strains. All these strains, however, may also oxidise the 7alpha-hydroxyl group beside dehydroxylating cholate. For this reason we assume that the conditions for the formation of deoxycholate are in general not existent in our experiments. The third degradation product, formed under anaerobic conditions, is probably a monohydroxy-monooxo-cholanoate, derived from deoxycholate. Structures of additional transformation products, occasionally found under aerobic incubation, which are all less polar than 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholanoic acid, could not be elucidated on account of minor amounts available. Bacteroides species are unable to transform the side chain of cholate, either as anaerobically growing cultures, or as aerobically incubated resting cells.

Aerobiosis↗

PubMedDate not supplied

An in vivo investigation of the negative chronotropic effect of cholic acid in the rat.

1. Experimental obstructive jaundice in the Wistar rat causes a significant decrease in heart rate. 2. Intravenous administration of cholic acid in vivo elicits a dose-dependent negative chronotropic effect. 3. Atropine or vagotomy significantly reduces, but does not abolish, the negative chronotropic effect of cholic acid. 4. Ganglion blockade and decerebration diminishes the negative chronotropic effect of cholic acid, but to a lesser extent than atropine or vagotomy. 5. Sympathetic depletion by reserpine slightly potentiates the response to cholic acid. 6. The effect of cholic acid injected cranially into the common carotid artery is less than when administered into the jugular vein. 7. The haemolysis caused by cholic acid does not appear to be involved in the negative chronotropic effect. 8. It is concluded that cholic acid causes both a direct as well as a vagally mediated negative chronotropic effect in the Wistar rat.

Animals↗

PubMed1983

Protoporphyrin hepatopathy. Effects of cholic acid ingestion in murine griseofulvin-induced protoporphyria.

Short-term effects of cholic acid ingestion on hepatic accumulation, fecal excretion, and blood levels of protoporphyrin were studied in vivo in griseofulvin-induced protoporphyric mice. Experimental mice that received feed with 2% griseofulvin and 0.5% cholic acid were compared with control mice that received feed with 2% griseofulvin for 4 wk. Five mice from each group were assessed each week for liver and blood porphyrin levels. Fecal protoporphyrin was compared weekly in the total pooled output of each population. Mean protoporphyrin levels were significantly lower for liver (P less than 0.0001), erythrocytes (P less than 0.05), and plasma (P less than 0.05), and higher for feces (P less than 0.001) for the mice that were fed cholic acid. Microscopic protoporphyrin deposits, inflammation, necrosis, and dysplasia were more severe in livers of control mice. A second experimental design compared four regimens in the feed given to all mice after 1-wk induction with 2% griseofulvin: (a) 0.5% cholic acid, (b) no adulterant, (c) 2% griseofulvin and 0.5% cholic acid, and (d) 2% griseofulvin. No difference in protoporphyrin removal from livers of mice in groups 1 and 2 was observed after 1 and 2 wk of these regimens. The apparent reduction in hepatic protoporphyrin content in mice of group 3 as compared with group 4 at weeks 2 and 3 was not significant at P less than 0.05. These data suggest that in selected circumstances, hepatic protoporphyrin secretion may be enhanced in protoporphyric disease states by bile salt supplementation.

Animals↗

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↗

PubMed1999

The effect of a combined dietary treatment with cholesterol and cholic acid on the lipid metabolism of geese at low or high choline concentrations.

A previous study demonstrated that a dietary treatment of young geese with cholesterol and cholic acid raises lipid concentrations in the liver. The present study was carried out to investigate whether such a lipid accumulation caused by those hyperlipidemic compounds can be intensified by low dietary choline concentrations. Therefore, 38 eight-week old geese were divided into four groups of 9 or 10 animals each and received a basal diet poor in choline which consisted predominately of maize and soy protein isolate over a period of 8 weeks. Treatment factors were supplementation of diets with cholesterol and cholic acid (0 vs. 5 g of cholesterol and cholic acid each per kg) and supplementation of choline chloride (0 vs. 1.5 g/kg). Final body weights as well as carcass weights were neither influenced significantly by dietary treatment with cholesterol and cholic acid nor by low dietary choline concentrations. However, feeding diets supplemented with cholesterol and cholic acid markedly increased liver weights (two-fold), hepatic triglyceride (3.7-fold) and cholesterol (12-fold) concentrations and percentages of monounsaturated fatty acids at the expense of saturated and polyunsaturated fatty acids in the liver. In geese fed diets with cholesterol and cholic acid, insufficient choline supply did not intensify, but even slightly reduced hepatic lipid accumulation. Geese fed diets with cholesterol and cholic acid exhibited markedly increased levels of cholesterol, triglycerides and phospholipids in plasma and very low-density lipoproteins, regardless of the choline supply. Muscle tissue of geese fed diets supplemented with cholesterol and cholic acid exhibited also increased concentrations of triglycerides and cholesterol whereas the fatty acid composition of muscle lipids remained unchanged. Among geese without hyperlipidemic treatment, concentrations of triglycerides in plasma and very low-density lipoproteins as well as the concentrations of phosphatidylcholine in liver and muscle tissue were not reduced by low dietary choline concentrations. Therefore, it is suggested that those animals were able to synthesize endogenous sufficient choline.

Animals↗

PubMedDate not supplied

Portal venous bile acids in cholesterol gallstone disease: effect of treatment with chenodeoxycholic and cholic acids.

We determined the serum concentrations of cholic, chenodeoxycholic and deoxycholic acids in portal and peripheral venous blood in 9 gallstone-free patients and 39 patients with cholesterol gallstones during standardized cholecystectomy. An accurate and specific gas chromatographic-mass spectrometric technique was used. The portal venous concentration of total bile acids was similar in gallstone-free and untreated gallstone patients (n = 20); there was no evidence of a reduced hepatic uptake of bile acids in the latter. Treatment with cholic acid (n = 10) was associated with a 70% increase in cholic acid and normal concentration of total bile acids. In chenodeoxycholic acid-treated patients (n = 9), the portal venous concentration of this bile acid was increased 3-fold; total bile acids were increased about 60%. The estimated hepatic uptake of cholic acid was slightly decreased during chenodeoxycholic acid treatment. The results indicate that neither bile acid inflow to the liver nor hepatic bile acid uptake is reduced in fasting patients with cholesterol gallstones, and treatment with chenodeoxycholic acid increases fasting inflow of bile acids to the liver. The latter may contribute to unsaturation of fasting hepatic bile during treatment with chenodeoxycholic acid.

Adult↗

PubMed1980

[Effect of cholic acid and chenodesoxycholic acid on biliary secretion in mice. Effect of the addition of beta-sitosterol].

Five groups of 20 mice received for 4 months one of the following diets: T, standard diet (T); a, T + cholic acid (0.2%); b, T + cholic acid (0.2%) + beta-sitosterol (2%); c, T + chenodeoxycholic acid (0.2%); d, T + chenodeoxycholic acid (0.2%) + beta-sitosterol (2%). After this time, the cholesterol intestinal absorption and the biliary secretion of lipids were measured. The biliary secretion of cholesterol, the total hepatic cholesterol (23 mg/g liver dry weight), and the intestinal absorption of cholesterol (90% administered dose) were higher in mice fed with cholic acid than in mice fed with chenodeoxycholic acid (hepatic cholesterol, 9.6 mg/g liver dry weight; absorption, 65% administered dose). The addition of beta-sitosterol to the diet supplemented with cholic acid decreased the cholesterol intestinal absorption and the biliary secretion of cholesterol so that both became similar to that obtained with chenodeoxycholic acid. These results indicate that in mice, as in man, cholic acid elicits a higher cholesterol biliary secretion than chenodeoxycholic acid. In this experimental model, the distinct effect on the biliary cholesterol of these two bile salts is due to their specific effects on the intestinal absorption of cholesterol.

Animals↗

PubMed1975

The metabolism of 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. An apparent inborn error of cholic acid synthesis.

Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of (3H)THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of (3H)cholic acid was also identified after (3H)THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3alpha, 7alpha, 12alpha, 24xi-tetrahydorxy-5beta-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid. This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal sibling nor the two parents have increased amount of THCA in their bile.

Adult↗

PubMed2007

Synthesis of novel cholic acid functionalized branched oligo/poly(epsilon-caprolactone)s for biomedical applications.

Novel cholic acid functionalized branched oligo/poly(epsilon-caprolactone)s were synthesized through the ring-opening polymerization of epsilon-caprolactone initiated by cholic acid with hydroxyl groups. The molecular weight of the branched polymers can be adjusted by controlling the feed ratio of the initiator cholic acid to the monomer epsilon-caprolactone. Comparing with linear homopolymer poly(epsilon-caprolactone) (PCL), these branched oligo/poly(epsilon-caprolactone)s show much faster hydrolytic degradation rates, implies that our approach provides a convenient and effective strategy to accelerate degradation of the biodegradable polymers with slow degradation rates such as PCL. The cell culture experiment indicates the incorporation of cholic acid moiety to the polymer chain can improve both cell adherence and proliferation obviously.

Animals↗

PubMed1983

Subcellular distribution of cholic acid:coenzyme a ligase and deoxycholic acid:Coenzyme a ligase activities in rat liver.

Cholic acid:CoA ligase (EC 6.2.1.7, choloyl-CoA synthetase) and deoxycholic acid:CoA ligase catalyze the synthesis of choloyl-CoA and deoxycholoyl-CoA from their respective bile acids in rat liver. A modification of the phase partition assay was introduced which yields significantly (3-fold) higher specific activities for cholic acid:CoA ligase than previously reported. An independent method of separating choloyl-CoA from the substrates by high-pressure liquid chromatography was also developed and validates the modification. Both enzymic activities were found to be localized predominantly in the endoplasmic reticulum of rat liver. The level of either ligase in other purified, active subcellular fractions is consistent with the level of contamination by endoplasmic reticulum, estimated by using marker enzymes. Hence, the ligase assay can be used as a sensitive enzymic marker for endoplasmic reticulum in rat liver. The kinetic parameters of both enzymic activities were determined by using purified rough endoplasmic reticulum from rat liver. While the apparent maximal velocities for the two substrates are similar, the Michaelis constant for deoxycholate is significantly lower than that for cholate. Taurocholate and deoxycholate are shown to be competitive inhibitors of cholic acid:CoA ligase. The inhibition constant of deoxycholate is similar to its Michaelis constant for the deoxycholoyl-CoA-synthesizing reaction, suggesting that the same enzyme is responsible for both ligase activities.

Animals↗

PubMed2000

Isolation and characterization of cholic acid 7alpha-dehydroxylating fecal bacteria from cholesterol gallstone patients.

BACKGROUND/AIMS: The development of cholesterol gallstones, in some patients, has been associated with increased proportions of deoxycholic acid in the bile acid pool. Deoxycholic acid is a microbial product of cholic acid 7alpha-dehydroxylation in the intestines. The levels and activities of bile acid 7alpha-dehydroxylating bacteria have been reported to be increased in gallstone patients. The aim of the current study was to isolate 7alpha-dehydroxylating bacteria from gallstone patients and determine if these individuals are colonized by similar bacterial species. METHODS: The levels of 7alpha-dehydroxylating bacteria in fecal samples were determined by fecal dilutions in 24 gallstone patients and 10 controls. 7alpha-Dehydroxylating bacteria were isolated by a non-selective streak plate technique and 7alpha-dehydroxylation activity was determined by measuring the conversion of [14C]-cholic acid to [14C]-deoxycholic acid using thin-layer chromatography. RESULTS: Gallstone patients had >42-fold (p<0.01) higher levels of 7alpha-dehydroxylating bacteria than patients who had not developed gallstones. Eighteen strains of 7alpha-dehydroxylating bacteria were isolated from eight gallstone patients. Attempts to isolate 7alpha-dehydroxylating bacteria from ten control patients were unsuccessful using identical isolation techniques. Surprisingly, all strains of bacteria isolated from gallstone patients appear to belong to the genus Clostridium. CONCLUSION: Gallstone patients have higher levels of 7alpha-dehydroxylating fecal bacteria and appear to harbor only members of the genus Clostridium with this activity.

Adult↗

PubMed1989

Cholic acid synthesis from 26-hydroxycholesterol and 3-hydroxy-5-cholestenoic acid in the rabbit.

Intravenous administration of 26-hydroxycholesterol to the rabbit with a bile fistula yielded cholic acid in proportions (84 and 86%) not significantly different from that derived from cholesterol. By contrast, the naturally occurring C27 bile acid 3 beta-hydroxy-5-cholestenoic acid yielded not more than 8% cholic acid. Thus initial 26-hydroxylation of cholesterol followed by 7-alpha-hydroxylation can provide sufficient amounts of cholic acid to be considered a quantitatively significant pathway for bile acid synthesis, and in addition it is the only pathway that can be the source of the circulating levels of C24 and C27 monohydroxy bile acids.

Animals↗

PubMed1979

Enterohepatic circulation rates of cholic acid and chenodeoxycholic acid in man.

The rate of enterohepatic cycling of cholic acid and chenodeoxycholic acid was determined in five male subjects. Pool sizes were measured by isotope dilution technique after intraduodenal administration of 14C-labelled cholic and chenodeoxycholic acid. The hourly hepatic secretion rate of bile acids was determined by an intestinal perfusion technique. From these data the cycling frequency was calculated. Chenodeoxycholic acid circulated on an average 1.34 (range, 1.13--1.57) times faster than cholic acid, probably because chenodeoxycholic acid to a larger extent than cholic acid is absorbed from the proximal small intestine and thus partly bypasses the hepaticoileal circuit. This difference in cycling rate may have methodological as well as physiological implications.

Bile Acids and Salts↗

PubMed1992

Biosynthesis of cholic acid accelerated by diabetes: its mechanism and effect of vanadate administration.

[7 beta-3H]3 alpha,7 alpha-Dihydroxy-5 beta-cholestane was infused into the femoral vein of bile-fistula rats. The main metabolites in bile were cholic, chenodeoxycholic, and alpha-muricholic acids. Cholic acid accounted for only 7.5% of the total biliary [3H]bile acids in the normal rats, but 51.8% in the diabetic rats. This increased proportion of cholic acid was partially cancelled by treatment of the diabetic rats with insulin (29.8%) or vanadate (28.8%). These results clearly confirm that an alternative biosynthetic pathway of cholic acid via 3 alpha,7 alpha-dihydroxy-5 beta-cholestane is accelerated by diabetes, and indicate that vanadate has an insulin-like effect on the formation of cholic acid in an insulin-deficient state.

Animals↗