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PubMed1987

Simultaneous determination of pool sizes and fractional turnover rates, of deoxycholic acid, cholic acid and chenodeoxycholic acid in man by isotope dilution with 2H and 13C labels and serum sampling.

This paper describes a method for simultaneous determination of the kinetics of the three major bile acids in man using (2,2,4,4-2H4) deoxycholic acid, (24-13C) cholic acid and (24-13C) chenodeoxycholic acid. The gas chromatographic/mass spectrometric-selected ion monitoring technique used provided complete separation of deoxycholic acid, cholic acid and chenodeoxycholic acid, which permitted simultaneous measurement of isotope ratios for all three bile acids. Since measurement of all three pool sizes and fractional turnover rates in a single experiment requires different isotopic labels for deoxycholic acid and cholic acid, we investigated the in vivo stability and applicability of (2,2,4,4-2H4) deoxycholic acid as a stable isotope marker for isotope dilution studies in man. No consistent differences were observed between deoxycholic acid pool sizes and fractional turnover rates determined in serum samples after administration of (2,2,4,4-2H4) deoxycholic acid and (24-13C) deoxycholic acid. Simultaneous administration of (2,2,4,4-2H4) deoxycholic acid, (24-13C) cholic acid and (24-13C) chenodeoxycholic acid and isotope ratio measurements in serum permitted determination of pool sizes and fractional turnover rates of the three major bile acid and the 7 alpha-dehydroxylation fraction. Pool sizes, fractional turnover rates and synthesis rates (input rates) agreed well with data obtained previously with (24-13C) labels in independent studies.

Carbon Isotopes↗

PubMed1989

7-Methyl bile acids: effects of chenodeoxycholic acid, cholic acid, and their 7 beta-methyl analogues on the formation of cholesterol gallstones in the prairie dog.

The purpose of this study was to compare the effects of the naturally occurring bile acids (chenodeoxycholic acid and cholic acid) with their 7-methyl analogues (3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid) on gallstone formation and prevention and cholesterol metabolism in the prairie dog. Sixty animals were fed a semipurified diet, containing 0.4% cholesterol, with one of the following acids (0.1%): chenodeoxycholic, cholic, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic, or 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid. This concentration of dietary bile acids amounts to a dose of 27-30 mg/kg.day. After 8 wk, 89% of control animals had gallstones and 94% had cholesterol crystals. Chenodeoxycholic and 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acids decreased the incidence of gallstones to 50%. Cholic acid and 3 alpha,7 alpha,12 alpha-tri-hydroxy-7 beta-methyl-5 beta-cholanoic acid did not prevent gallstone formation. The liver cholesterol level was decreased by chenodeoxycholic acid, whereas cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids increased serum and liver cholesterol. Each administered bile acid became the predominant biliary bile acid and 7-methyl analogues did not increase secondary bile acids. Fecal analysis of radioactive metabolites using 14C-labeled 7-methyl analogues showed that these compounds are resistant to bacterial 7-dehydroxylation. It was concluded that 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid inhibited gallstone formation as effectively as chenodeoxycholic acid, whereas both cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids were not effective. The effects of 7-methyl analogues on the parameters of cholesterol metabolism that we studied were similar to those of their parent compounds, chenodeoxycholic and cholic acids. Thus, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid but not 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid offers promise in cholelitholytic therapy for the prevention and possibly dissolution of cholesterol gallstones.

Animals↗

PubMed1996

Delta 4-3-oxosteroid 5 beta-reductase deficiency: failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid.

BACKGROUND: In some infants with liver disease, 3-oxo-delta 4 bile acids are the major bile acids in urine, a phenomenon attributed to reduced activity of the delta 4-3-oxosteroid 5 beta-reductase required for synthesis of chenodeoxycholic acid and cholic acid. These patients form a heterogeneous group. Many have a known cause of hepatic dysfunction and plasma concentrations of chenodeoxycholic acid and cholic acid that are actually greater than those of the 3-oxo-delta 4 bile acids. It is unlikely that these patients have a primary genetic deficiency of the 5 beta-reductase enzyme. AIMS: To document the bile acid profile, clinical phenotype, and response to treatment of an infant with cholestasis, increased plasma concentrations of 3-oxo-delta 4 bile acids, low plasma concentrations of chenodeoxycholic acid and cholic acid, and no other identifiable cause of liver disease. PATIENTS: This infant was compared with normal infants and infants with cholestasis of known cause. METHODS: Analysis of bile acids by liquid secondary ionisation mass spectrometry and gas chromatography-mass spectrometry. RESULTS: The plasma bile acid profile of the patient was unique. She had chronic cholestatic liver disease associated with malabsorption of vitamins D and E and a normal gamma-glutamyltranspeptidase when the transaminases were increased. The liver disease failed to improve with ursodeoxycholic acid but responded to a combination of chenodeoxycholic acid and cholic acid. CONCLUSION: Treatment of primary 5 beta-reductase deficiency requires the use of bile acids that inhibit cholesterol 7 alpha-hydroxylase.

Bile Acids and Salts↗

PubMed1981

Biosynthesis of bile acids in man. An in vivo evaluation of the conversion of R and S 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic and 3 alpha, 7 alpha, 12 alpha-24 xi-tetrahydroxy-5 beta-cholestanoic acids to cholic acid.

In vivo studies were carried out on three bile fistula patients to further elucidate the side chain oxidation pathways from C-27 bile acids to cholic acid in man. Two patients each received (25-R)- and (25-S)-3 alpha, 7 alpha,-12 alpha-trihydroxy-5 beta-[7 beta-3H]cholestanoic acid (THCA) on consecutive days and three patients wee administered 3 alpha, 7 alpha, 12 alhpa, 24 xi-tetrahydroxy-5 beta-[7 beta-3H]cholestanoic acid (varanic acid). The varanic acid was biosynthetically prepared with rat liver microsomes and was probably the 24 alpha isomer. The patients efficiently (84 to 97%) converted both (R)- and (S)-THCA to cholic acid. There was no apparent significant difference in the ability of either (R)- or (S)-THCA to form cholic acid. Varanic acid was poorly converted (20 to 27%) to cholic acid in all three patients. From 49 to 75% of the administered 3H activity was recovered in the bile as other labeled products. The bulk (30 to 35%) of this 3H activity was identified by thin layer chromatography as varanic acid. The rate of conversion of (R)-THCA, (S)-THCA, and varanic acid was extremely rapid in all three patients with a t 1/2 of 35 to 74 min. The findings suggest that (a) the stereospecific configuration at C-25 of THCA has no significant effect on the efficiency of side chain oxidation to cholic acid; and (b) side chain cleavage pathways may exist which do not pass through varanic acid, or the oxidation of varanic acid in man is highly stereospecific with respect to the hydroxyl group at C-24. To prove the latter, it will be necessary to compare the metabolism of the 24 alpha and 24 beta isomers of varanic acid.

Bile↗

PubMed1989

Identification of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholest-24-enoic acid as an intermediate in the peroxisomal conversion of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid to cholic acid.

In this study, we have identified a delta 24-unsaturated intermediate involved in the conversion of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid to cholic acid by the peroxisomal fraction of rat liver. An accumulation of this intermediate was observed when NAD+ was omitted from the reaction mixture. The intermediate was isolated by reversed-phase high-pressure liquid chromatography and identified by combined gas-liquid chromatography-mass spectrometry. The peroxisomal fraction was able to catalyze the conversion of the delta 24-unsaturated intermediate to cholic acid in the presence of CoA, ATP, Mg2+ and NAD+. The identification of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholest-24-enoic acid in cholic acid formation supports the proposed reaction mechanism in which the side-chain cleavage of C27-steroids is similar to that of peroxisomal beta-oxidation of fatty acids. This involves an FAD-dependent oxidase acting on 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoyl-CoA.

Adenosine Triphosphate↗

PubMed1982

The enzymic and chemical synthesis of ursodeoxycholic and chenodeoxycholic acid from cholic acid.

Three approaches to the synthesis of ursodeoxycholic acid (UDC) from cholic acid have been investigated: (i) oxidation of cholic acid to 3 alpha, 7 alpha-dihydroxy-12 keto-5 beta-cholanoic acid (12K-CDC) with Clostridium group P 12 alpha-hydroxysteroid dehydrogenase (HSDH), isomerization of 12K-CDC to 3 alpha, 7 beta-dihydroxy-12 keto-5 beta-cholanoic acid (12K-UDC) with Clostridium absonum 7 alpha- and 7 beta-HSDH and reduction of 12K-UDC by Wolff-Kishner to UDC; (ii) isomerization of cholic acid to ursocholic acid (UC) by C. absonum 7 alpha- and 7 beta-HSDH, oxidation of UC to 12K-UDC with Clostridium group P 12 alpha-HSDH and Wolff-Kishner reduction of 12K-UDC to UDC; (iii) oxidation of cholic acid to 12K-CDC by Clostridium group P 12 alpha-HSDH, Wolff-Kishner reduction of 12K-CDC to chenodeoxycholic acid (CDC) and isomerization of CDC to UDC using whole cell cultures of C. absonum. In the first two approaches (using cell free systems) the yields of desired product were relatively low primarily due to the formation of various side products. The third method proved the most successful giving an overall yield of 37% (UDC) whose structure was verified by mass spectroscopy of the methyl ester.

Cells, Cultured↗

PubMed1989

Effect of coinfusion of cholic acid and sulfated cholic acid on bile formation in rats.

The effect of combined infusion of sulfated cholic acid and nonsulfated cholic acid on bile formation was investigated. The data show that the secretion of sulfated cholic acid is slower and does not share the same transport mechanism(s) as nonsulfated cholic acid. Sulfated cholic acid significantly increased bile flow and reduced the secretion of biliary phospholipids, cholesterol, and protein associated with the secretion of exogenous nonsulfated cholic acid, only when they were infused in a ratio higher than 2:1 (sulfated:nonsulfated). Thus it is concluded that sulfated bile acids may protect the liver against the toxic effect of high concentration of bile acids. The relevance of these findings to human cholestasis remains to be determined because sulfated bile acids do not predominate in serum during cholestasis.

Animals↗

PubMed1989

Mechanism of intestinal formation of deoxycholic acid from cholic acid in humans: evidence for a 3-oxo-delta 4-steroid intermediate.

12 alpha-Hydroxy-3-oxo-4-cholenoic acid coupled to an adenosine nucleotide has been shown to be a metabolite of cholic acid in the intestinal anaerobic bacteria, Eubacterium species VPI 12708 (1987. J. Biol. Chem. 262: 4701-4707) and it has been suggested that this may be an intermediate in the conversion of cholic acid into deoxycholic acid. The possibility that the intestinal conversion of cholic acid into deoxycholic acid involves a 3-oxo-delta 4-steroid as an intermediate has been studied in the present work by use of [3 beta-3H]- and [5-3H]-labeled cholic acid. Whole cells as well as cell extracts of Eubacterium sp. VPI 12708 catalyzed conversion of [3 beta-3H] + [24-14C]cholic acid into deoxycholic acid with loss of about 50% of 3H label. When unlabeled chenodeoxycholic acid (20 microM) was added along with [3 beta-3] + [24-14C]cholic acid, then approximately 85% of the [3 beta-3H]-labeled was lost from deoxycholic acid. After administration of the same mixture to two healthy volunteers, deoxycholic acid could be isolated that had lost 81 and 84%, respectively, of the 3H label. Conversion of a mixture of [5-3H]- and [24-14C]labeled cholic acid by the above intestinal bacteria or cell extracts led to loss of 79-94 of the [5-3H] label.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1975

Bile acid metabolism in mammals: IX. Conversion of chenodeoxycholic acid to cholic acid by isolated perfused rat liver.

Current dogma of bile acid synthesis in mammals insists that hydroxylation of the ring structure at C-12 precedes side chain oxidation, and that chenodeoxycholic acid is not converted to cholic acid under normal conditions. This report concerns the conversion of chenodeoxycholic acid to cholic acid by isolated, perfused rat liver. Results indicate that isolated perfused rat liver has a definite, but limited, capacity for synthesis of cholic acid from chenodeoxycholic acid.

Animals↗

PubMed1993

Stereochemistry of intermediates in the conversion of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid to cholic acid by rat liver peroxisomes.

We have investigated the stereochemistry of the side chain of the intermediates, 3 alpha, 7 alpha,12 alpha-trihydroxy-5 beta-cholest-24-enoic acid and 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestanoic acid, in the conversion of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid to cholic acid by rat liver peroxisomes. The intermediates formed were converted to the p-bromophenacyl ester derivatives and analyzed by reversed-phase high-performance liquid chromatography. Only the (24E) form of the two isomers of the delta 24-unsaturated acid and the (24R,25S) form of the four isomers at C-24 and C-25 of the 24-hydroxy acid were found to be formed stereospecifically from either (25R)- or (25S)-3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid. Formation of the other isomers of the alpha beta-unsaturated bile acid or the beta-hydroxy bile acid was not detected. The findings support the proposed pathway for the side-chain cleavage in cholic acid biosynthesis, which is thought to be similar to that of peroxisomal fatty acid beta-oxidation.

Animals↗

PubMed1976

[Effect of ursodesoxycholic acid and cholic acid on intestinal absorption of cholesterol].

A study was carried out to investigate the effect of ursodesoxycholic acid and cholic acid on intestinal absorption of cholesterol-4-14C administered p.o. to lymph-fistula rats. The results indicated that within 24 hours, the labeled cholesterol detected in thoracic duct lymph of the control group was 21.0% of the administered cholesterol-4-14C, whereas the group treated with cholic acid (250 mg/kg p.o.) was found to have an increased value of 30.6% absorbed cholesterol. In comparison, the group treated with the same dose of ursodesoxycholic acid showed a decreased value of 12.1%, indicating an inhibitory effect on cholesterol absorption by the compound. This differential effect of the two compounds was also observed in a time-course study.

Animals↗

PubMed1978

Effect of taurocholate on the conversion of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid into cholic acid.

To determine if the conversion of the intermediate, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid is influenced by taurocholate, two rats were infused intravenously with [3H] THCA until they reached a steady state. Taurocholate was then added and infused at a rate of 1 mumole/min/rat for 48 hours. The percentage of [3H] THCA recovered in the bile did not increase indicating that taurocholate does not suppress the conversion of THCA into cholic acid.

Animals↗

PubMed1990

Studies on the origin of biliary phospholipid. Effect of dehydrocholic acid and cholic acid infusions on hepatic and biliary phospholipids.

The correlation between the secretion of biliary phospholipid (PL) and bile acid suggests a regulatory effect of bile acid on PL secretion. Bile acids may influence PL synthesis and/or the mobilization of a preformed PL pool. The objective of this study was to determine the contribution of these two sources to biliary PL, by using an experimental protocol in which dehydrocholic acid (DHCA) and cholic acid (CA) were infused to manipulate biliary PL secretion. In control rats, there was a steady state in bile flow. PL secretion and the biliary secretion of newly synthesized phosphatidylcholine (PC). The specific radioactivity of PC in bile was significantly higher than in plasma, microsomes and canalicular membranes. DHCA infusion decreased biliary PC secretion rate by 80%, and secretion returned to normal values at the transport maximum of CA. The specific radioactivity of biliary PC was decreased by 30% by DHCA infusion and reached normal values during CA infusion. There were no significant changes in the specific radioactivity of PC in plasma or cellular organelles during infusion of bile acids. These data indicate that: (1) newly synthesized PC contributes a small percentage to biliary PC; thus a preformed pool (microsomal and extrahepatic) is a major source of biliary PL; (2) the contribution of the extrahepatic pool to the biliary PL may be more important than the microsomal pool.

Animals↗

PubMed1975

[Conjugation of chenodeoxycholic acid and cholic acid during passage through liver].

Both chenodeoxycholic acid, in the dosage administered for dissolution of gallstones, and cholic acid are completely conjugated during one passage through the liver. The glycine:taurine ratio increases with the cumulative amount of exogenous bile acids secreted, which suggests consumption of available taurine. Since conjugation with glycine compensates for deficiency of the taurine conjugating system, it can be assumed that in the normal liver and with doses not exceeding 2.5 mmoles, chenodeoxycholic acid is efficiently and completely transformed into its "physiologic" conjugated form.

Bile Acids and Salts↗

PubMed1987

7-Methyl bile acids: 7 beta-methyl-cholic acid inhibits bacterial 7-dehydroxylation of cholic acid and chenodeoxycholic acid in the hamster.

The effect of dietary 7 beta-methyl-cholic acid [0.075% in rodent chow (6.4 mg/animal per day)] on cholesterol and bile acid metabolism was studied and compared with that of cholic acid in the hamster. Following oral administration of 7 beta-methyl-cholic acid for 3 weeks, the glycine-conjugated bile acid analog became a major constituent of gallbladder bile. Biliary cholic acid concentration decreased significantly, while that of chenodeoxycholic acid remained unchanged. Serum and liver cholesterol levels were increased by dietary 7 beta-methyl-cholic acid and by cholic acid. Hepatic microsomal HMG-CoA reductase activity was inhibited (30% of the control value) by both bile acids; cholesterol 7 alpha-hydroxylase activity was not affected. In chow controls and cholic acid-fed animals, bacterial 7-dehydroxylation of [14C]chenodeoxycholic acid and [14C]cholic acid was nearly complete. In contrast, dietary 7 beta-methyl-cholic acid effectively prevented the 7-dehydroxylation of the two primary bile acids. These results show that dietary 7 beta-methyl-cholic acid is preserved in the enterohepatic circulation and has an effect on serum and liver cholesterol concentrations similar to those produced by the naturally occurring cholic acid. 7 beta-Methyl-cholic acid is an efficient inhibitor of the bacterial 7-dehydroxylation of the primary bile acids in the hamster.

Animals↗

PubMed1994

Uptake of taurocholic acid and cholic acid in isolated hepatocytes from rainbow trout.

The uptake of the bile acids cholate (CHA) and taurocholate (TCHA) was studied in isolated hepatocytes from rainbow trout (Oncorhynchus mykiss). Both CHA and TCHA were taken up in a concentration- and temperature-dependent manner with optimum temperature at 15 degrees C and a strikingly efficient uptake even at low temperatures (0-5 degrees C). The total uptake was a combination of a saturable [Michaelis-Menten constant (Km) for CHA, 20 microM; Km for TCHA, 19 microM] and a nonsaturable component. The maximal uptake rate of the saturable component was 416 and 805 pmol.mg protein-1.min-1 for CHA and TCHA, respectively. The uptake of both bile acids was shown to be energy dependent, since it was inhibited by the metabolic inhibitors antimycin A, oligomycin and carbonyl cyanide m-chlorophenylhydrazone. The uptake was clearly Na+ independent, since isosmotic replacement of extracellular Na+ by Li+, choline, or K+ did not inhibit the uptake. Furthermore, it seemed to be independent of the presence of extracellular Cl-, since it was not inhibited by replacement of Cl- with sodium gluconate. On the whole, our results show that the hepatocellular uptake of bile acids in rainbow trout is mediated by a Na(+)-independent carrier system, with characteristics resembling the corresponding transport component in mammalian hepatocytes, but with high efficiency even at low temperatures.

Animals↗

PubMedDate not supplied

Enhanced transepithelial transport of peptides by conjugation to cholic acid.

The potential of the intestinal bile acid transporter to serve as a shuttle for small peptide molecules was investigated. Eleven peptides with a 2-6 amino acid backbone were conjugated to the 24-position of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholan-24-oic acid (cholic acid) via an amide bond using an automated peptide synthesizer. In a human intestinal cell line (CaCo-2), cholic acid-peptide conjugates were able to inhibit the transepithelial transport of [3H]taurocholic acid, a natural substrate for the bile acid carrier, at a 100:1 conjugate/substrate ratio. Affinity for the carrier decreased significantly when the conjugate in the 24-position increased from 1 to 2 amino acids. Further increase in the amino acid chain length caused only minor decrease in affinity. A tetrapeptide-bile acid conjugate, [3H]-ChEAAA (Ch = cholic acid), was transported by the bile acid transporter, showing markedly higher apical (AP)-to-basolateral (BL) compared to BL-to-AP transport and inhibition by a 100-fold excess taurocholic acid. Another conjugate with 6 amino acids (ChEASASA) was transported by a passive diffusion pathway but still showed higher transport rates than the passive permeability marker mannitol, suggesting the possibility that the cholic acid moiety aids the passive membrane transfer of peptide molecules by increasing its lipophilicity. Metabolism of bile acid-peptide conjugates in CaCo-2 cells was 3% over 3 h. In conclusion, these studies show that the coupling of peptides to the 24-position of the sterol nucleus in cholic acid results in a combination of decreased metabolism and increased intestinal absorption, either by a carrier-mediated pathway or by accelerated passive diffusion.

Biological Transport↗

PubMed1994

Non-stereoselective formation of 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestan-26-oic acid during cholic acid biosynthesis.

Incubation of (25RS)-, (25R)- and (25S)-3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid (THCA, 6, 6a, 6b) and (24E)-3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholest-24-en-26-oic acid (7) with rat liver mitochondria gave all four stereoisomers (9a,9b,9c,9d) of 3 alpha,7 alpha,12 alpha,24-Tetrahydroxy-5 beta-cholestan-26-oic acid (TeHCA). The corresponding 27-nor analogs (10,11) were also converted non-stereoselectively to a 1:1 mixture of the epimeric 24-hydroxy compounds (12).

Animals↗