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PubMed1994

Identification of (24E)-3 alpha,7 alpha-dihydroxy-5 beta-cholest-24-enoic acid and (24R,25S)-3 alpha,7 alpha,24-trihydroxy-5 beta-cholestanoic acid as intermediates in the conversion of 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid to chenodeoxycholic acid in rat liver homogenates.

Studies of chemical structure of the intermediates in the biosynthetic sequence between 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid (DHCA) and chenodeoxycholic acid have been undertaken. Radiolabeled DHCA was incubated with a rat liver preparation. The reaction products were converted to the p-bromophenacyl esters, and analyzed by reversed-phase high performance liquid chromatography. Under the conditions used, the radioactivity was found in (24E)-3 alpha,7 alpha-dihydroxy-5 beta-cholest-24-enoic acid (31%) and (24R,25S)-3 alpha,7 alpha,24-trihydroxy-5 beta-cholestanoic acid (7%) along with the starting material (62%). Neither the 24Z isomer of the alpha,beta-unsaturated bile acid nor the other three isomers of the beta-hydroxy bile acid were detected. The findings support the proposed pathway for the side chain cleavage in chenodeoxycholic acid biosynthesis, which is thought to be identical to that of cholic acid biosynthesis.

Animals↗
PubMed1980

Cholic acid and chenodeoxycholic acid concentrations in serum during infancy and childhood.

Concentrations of two primary bile acids (cholic and chenodeoxycholic acids) were determined by radioimmunoassay in the serum of infants and children at ages ranging from 1 hour to 15 years. The same bile acids were also measured in umbilical cord serum. Concentrations of the primary bile acids were significantly higher in the serum of 1-hour old infants than those in the umbilical cord serum or the peripheral vein serum of adults. The levels of cholic and chenodeoxycholic acid remained high until the age of 6 months, being about 5-fold higher than those in the sera of adults. Primary bile acid concentrations reached the adult level by the age of 1-2 years. These results indicate that developmental changes occur in the metabolism and excretion of bile acids in man. The relatively high concentrations of the primary bile acids in serum during the first 6 months of life suggest that up to this age, the mature ability of the liver to excrete the bile salts into the bile and/or to clear them from the circulation has not yet been reached.

Adolescent↗
PubMed1991

Bile acids of marsupials. 2. Hepatic formation of vulpecholic acid (1 alpha,3 alpha,7 alpha-trihydroxy-5 beta-cholan-24-oic acid) from chenodeoxycholic acid in a marsupial, Trichosurus vulpecula (Lesson).

Free vulpecholic acid (1 alpha,3 alpha,7 alpha-trihydroxy-5 beta-cholan-24-oic) is the major biliary component of the Australian opossum (Trichosurus vulpecula), accompanied only by a few percent of its taurine conjugate. In order to exclude a microbial involvement in its formation (i.e., secondary origin) four sets of experiments were performed. It was found that a) the level of vulpecholic acid remained unchanged in the bile of opossums fed with neomycin and kanamycin for 7 days prior to bile collection; b) it also remained unchanged after long bile drainage; c) in opossums prepared with biliary cannula, intraportally injected [24-14C]chenodeoxycholic acid was transformed to [24-14C]vulpecholic acid; and d) in a similar experiment, the detectable transformation of [1 alpha,2 alpha-3H2]cholesterol to vulpecholic acid was observed. In experiment c) 28-66% of the administered radioactivity was secreted in 2 h in the form of free biliary vulpecholic and chenodeoxycholic acids. Only a trace amount of the corresponding taurine conjugates (approximately 0.4%) was formed. Moreover, rapidly declining specific radioactivity of the unconjugated chenodeoxycholic acid indicated its probable participation in the native formation of vulpecholic acid.

Animals↗
PubMed1982

Formation of ursodeoxycholic acid from chenodeoxycholic acid by a 7 beta-hydroxysteroid dehydrogenase-elaborating Eubacterium aerofaciens strain cocultured with 7 alpha-hydroxysteroid dehydrogenase-elaborating organisms.

A gram-positive, anaerobic, chain-forming, rod-shaped anaerobe (isolate G20-7) was isolated from normal human feces. This organism was identified by cellular morphology as well as fermentative and biochemical data as Eubacterium aerofaciens. When isolate G20-7 was grown in the presence of Bacteroides fragilis or Escherichia coli (or another 7 alpha-hydroxysteroid dehydrogenase producer) and chenodeoxycholic acid, ursodeoxycholic acid produced. Time course curves revealed that 3 alpha-hydroxy-7-keto-5 beta-cholanoic acid produced by B. fragilis or E. coli or introduced into the medium as a pure substance was reduced by G20-7 specifically to ursodeoxycholic acid. The addition of glycine- and taurine-conjugated primary bile acids (chenodeoxycholic and cholic acids) and other bile acids to binary cultures of B. fragilis and G20-7 revealed that (i) both conjugates were hydrolyzed to give free bile acids, (ii) ursocholic acid (3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acid) was produced when conjugated (or free) cholic acid was the substrate, and (iii) the epimerization reaction was at least partially reversible. Corroborating these observations, an NADP-dependent 7 beta-hydroxysteroid dehydrogenase (reacting specifically with 7 beta-OH-groups) was demonstrated in cell-free preparations of isolate G20-7; production of the enzyme was optimal at between 12 and 18 h of growth. This enzyme, when measured in the oxidative direction, was active with ursodeoxycholic acid, ursocholic acid, and the taurine conjugate of ursodeoxycholic acid (but not with chenodeoxycholic, deoxycholic, or cholic acids) and displayed an optimal pH range of 9.8 to 10.2

Bacteroides fragilis↗
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↗
PubMed1991

Abnormal low ratio of cholic acid to chenodeoxycholic acid in a cholestatic infant with severe hypoglycemia.

We report a premature infant with severe hypoglycemia (serum glucose: 6 mg/dl) and cholestasis (serum total bile acids: 211.55 mumol/L) caused by hypoplasia of the interlobular bile ducts. This patient had developed intracranial hemorrhage and sepsis while undergoing treatment for hypoglycemia. As a result of endocrine evaluation, we made a diagnosis of idiopathic panhypopituitarism, congenital absence or hypoplasia of the pituitary gland. Moreover, we found abnormal bile acid profiles: The ratio of cholic acid to chenodeoxycholic acid was abnormally low in serum (0.04) and in biliary bile (0.33). However, 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid and bile alcohols were not detected. We therefore suspected that the severe cholestasis and abnormal bile acid profiles in the serum and biliary bile in this patient were related to physiologic immaturity of the enterohepatic circulation of bile acids and immaturity of hepatic 12 alpha-hydroxylation.

Adult↗
PubMed2004

Bioconversion of 3beta-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems.

We have previously demonstrated that the rat brain contains three unconjugated bile acids, and chenodeoxycholic acid (CDCA) is the most abundantly present in a tight protein binding form. The ratio of CDCA to the other acids in rat brain tissue was significantly higher than the ratio in the peripheral blood, indicating a contribution from either a specific uptake mechanism or a biosynthetic pathway for CDCA in rat brain. In this study, we have demonstrated the existence of an enzymatic activity that converts 3beta-hydroxy-5-cholenoic acid into CDCA in rat brain tissue. To distinguish marked compounds from endogenous related compounds, 18O-labeled 3beta-hydroxy-5-cholenoic acid, 3beta,7alpha-dihydroxy-5-cholenoic acid, and 7alpha-hydroxy-3-oxo-4-cholenoic acid were synthesized as substrates for in vitro incubation studies. The results clearly suggest that 3beta-hydroxy-5-cholenoic acid was converted to 3beta,7alpha-dihydroxy-5-cholenoic acid by microsomal enzymes. The 7alpha-hydroxy-3-oxo-4-cholenoic acid was produced from 3beta,7alpha-dihydroxy-5-cholenoic acid by the action of microsomal enzymes, and Delta4-3-oxo acid was converted to CDCA by cytosolic enzymes. These findings indicate the presence of an enzymatic activity that converts 3beta-hydroxy-5-cholenoic acid into CDCA in rat brain tissue. Furthermore, this synthetic pathway for CDCA may relate to the function of 24S-hydroxycholesterol, which plays an important role in cholesterol homeostasis in the body.

Animals↗
PubMed1984

Simultaneous determination of cholic acid and chenodeoxycholic acid pool sizes and fractional turnover rates in human serum using 13C-labeled bile acids.

A method has been developed for simultaneous determination of pool sizes and fractional turnover rates (FTR) of chenodeoxycholic acid (CDCA) and cholic acid (CA) in man by 13C/12C isotope ratio measurements of bile acids in serum after oral administration of 20-50 mg of [24-13C]-labeled bile acids. 13C/12C isotope ratio measurements were performed by capillary gas-liquid chromatography/electron impact mass spectrometry. CA and CDCA kinetics in serum measured by this method exhibited first order kinetics and permitted calculation of pool size and FTR of CA and CDCA. The validity of the measurements in serum was tested by simultaneous measurements in bile in three healthy volunteers and in five patients with various hepatobiliary disorders (three patients with cirrhosis, one with cholecystectomy and sphincterotomy, and one with sphincterotomy only). No consistent differences were found between the pool sizes and FTR's obtained from serum and bile. In a total of five healthy volunteers bile acid kinetics were measured in serum. The values found for the pool sizes and FTR's of CA and CDCA in these subjects were in excellent agreement with data reported in the literature based on 14C or 3H measurements in bile. The pool sizes (mean +/- SD) of CDCA and CA were 32.6 +/- 9.9 and 31.8 +/- 16.0 mumol X kg-1, respectively. The corresponding values for the FTR's were 0.24 +/- 0.13 and 0.48 +/- 0.22 d-1. These data demonstrate that pool sizes and fractional turnover rates of cholic and chenodeoxycholic acid can be measured simultaneously by blood sampling after oral administration of the respective 13C-labeled bile acids.

Adult↗
PubMed1990

Cholic acid and chenodeoxycholic acid transport in the hepatic acinus in rats. Effect of necrosis of zone 3 induced by bromobenzene.

The transport of cholic acid (CA) and chenodeoxycholic acid (CDC) and their influence on bile formation was investigated in rats treated with bromobenzene (BZ), a toxicant which selectively destroys zone 3 of the hepatic acinus. The necrosis equals 27-31% of the acinus cells. The absence of zone 3 in rats reduced the secretory rate maximum of CA and CDC by 18% (NS) and 25% (p less than 0.05), respectively. The maximum bile flow was not different from control during CA infusion but was lower during CDC infusion in BZ-treated animals. Although the bile acid concentration was lower in BZ-treated rats, only values obtained during the basal period and the beginning of the infusion reached the level of statistically significant difference. The bile salt-independent flow (BSIF) was not affected by the absence of zone 3. Our data suggest that zones 1 and 2 of the hepatic acinus can compensate for the secretion of CA and elaboration of BSIF when zone 3 is destroyed. However, necrosis of zone 3 reduces CDC secretion. Thus, the capacity for bile acid transport of the hepatocytes of different zones in the hepatic acinus may differ according to the circulating bile acid.

Animals↗
PubMed2005

Polymorphism in the coding part of the sterol 12alpha-hydroxylase gene does not explain the marked differences in the ratio of cholic acid and chenodeoxycholic acid in human bile.

OBJECTIVE: In humans, two primary bile acids are synthesized: cholic acid (CA) and chenodeoxycholic acid (CDCA), the first and rate-limiting enzyme being cholesterol 7alpha-hydroxylase (CYP7A1). CA has one more hydroxyl group at position 12alpha. This hydroxylation is carried out by the sterol 12alpha-hydroxylase (CYP8B1). Earlier, we and others have noticed a marked variation in the ratio between CA and CDCA in human bile. The aim of this study was to investigate whether this marked difference could be due to a genetic polymorphism in the gene of the CYP8B1. MATERIAL AND METHODS: Screening for genetic polymorphisms was carried out in a 2.4-kb-long area including the exon and part of the promoter region in subjects who had undergone cholecystectomy earlier, and where bile acid analysis had been performed. Among these subjects those with very high or low CA/CDCA ratios (ranging from 0.9 to 6.8) were investigated. The subjects were all female, normolipidaemic, having normal weight and a normal thyroid function. RESULTS: No polymorphisms were found in the investigated sequence. However, a statistically significant correlation was found between the activity of the CYP7A1 and the ratio between CA and CDCA. The difference in ratio could, at least in part, be explained by the difference in rate of bile acid synthesis. CONCLUSION: The difference in ratio between CA and CDCA cannot be explained by a polymorphism in the coding area of the CYP8B1.

Adult↗
PubMed1996

[Interrelationship of reflux bile acid concentration and the gastric mucosal change with reference to the pathophysiologic significance of taurine conjugated deoxycholic acid and chenodeoxycholic acid].

Since chronic gastritis is adversely affected by reflux bile acids, we are interested in which of these bile acids cause the most damage to the gastric mucosa as ulcerogenic factors in the stomach. We examined 34 patients suffering from the peptic ulcers, and have assumed that taurine conjugated deoxycholic acid (TDC) and chenodeoxycholic acid (TCDC) may act as the mst ulcerogenic factors. Moreover TCDC was suggested to be associated with the cystic dilatation of the gastric gland. It was also suggested that TDC is involved in the increased frequency of intestinal metaplasia as a factor backgrounding cancer.

Adult↗
PubMed1995

[Determination of ursodeoxycholic acid and chenodeoxycholic acid in Chinese medicinal compound preparations by TLC-densitometry].

The contents of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in Chinese medicinal compound preparations have been determined by TLC-densitometry. The determination wavelength was 375nm and reference wavelength was 700nm. For UDCA the linear range was 3.0-15.0 micrograms and recovery was 97.2% (RSD = 1.2%), and for CDCA the linear range was 4.0-20.0 micrograms and recovery was 99.3% (RSD = 2.1%).

Animals↗
PubMed1993

[In vitro analysis for cellular toxicity of polychlorinated biphenyls (PCBs) and 2,3,4,7,8-pentacholorodibenzofuran (PCDF) on PLC/PRF/5 cell proliferation (II)--The effects of ursodeoxycholic acid and chenodeoxycholic acid on cell toxicity].

We investigated the cell toxicity of polychlorinated biphenyls (PCBs) and 2,3,4,7,8-pentachlorodibenzofuran (PCDF) as two kinds of indicator of the quantity of secreting protein, which is an HBV surface antigen (HBsAg) in PLC/PRF/5 cells, and the DNA of those cells was counted the radioactivity for dot hybridization method, respectively. Furthermore, the reductive action of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on the PCBs and PCDF toxicity was investigated. HBsAg titer increased to 10 to 15% with the addition of CDCA at the concentration of 0.02 x 2(-6)%. However, the slope of the curve of DNA synthesis of HeLa cells at the presence of PCDF was gradually increased at the concentration of 0.02 x 2(-4)% of UDCA and CDCA, and it became to overlap with a control group while PCBs did not. These results mean that PCDF cell toxicity was suppressed a little by UDCA and CDCA, but the case of PCBs did not.

Benzofurans↗
PubMed1981

Molecular species of biliary phosphatidylcholines in gallstone patients: the influence of treatment with cholic acid and chenodeoxycholic acid.

Molecular species of phosphatidylcholines were analyzed in hepatic and gallbladder bile obtained from six subjects with adenomyoma of the gallbladder (gallstone-free controls) and 27 gallstone patients undergoing cholecystectomy. Seven of the gallstone patients had been treated with cholic acid and seven with chenodeoxycholic acid for at least 8 weeks before operation. The two predominant species were 1-palmitoyl-2-oleoyl- and 1-palmitoyl-2-linoleoyl-sn-glycerophosphocholines which together accounted for 75-80% of the total amount of phosphatidylcholines. Minor species were 1-palmitoyl-2-palmitoleoyl-, 1-stearoyl-2-linoleoyl-, 1-oleoyl-2-linoleoyl-, and 1-palmitoyl-2-arachidonoyl-sn-glycerophosphocholines. Gallstone patients had a higher portion of the 1-palmitoyl-2-oleoyl species and a concomitant lower proportion of the 1-palmitoyl-2-linoleoyl species than gallstone-free subjects. The ratio between the two species was about 0.7 and 0.4, respectively, in the hepatic bile of the two groups of patients. Treatment with bile acids was associated with a normalization of the pattern of phosphatidylcholines.

Bile↗
PubMed1977

Speed of change in biliary lipids and bile acids with chenodeoxycholic acid--is intermittent therapy feasible?

To see whehter intermittent chenodeoxycholic acid (CDCA) therapy is a potential alternative to continous treatment for gallstone dissolution, the speed of change in bile lipid composition was studied after starting and stopping CDCA therapy. In addition, the relationship between bile lipid composition and the proportions of the bile acids was examined. Bile-rich duodenal fluid was collected twice in the first week and then at approximately weekly intervals for four to six weeks, from six gallstone patients starting 13-15 mg CDCA.kg BW-1 day-1 and from another group of six patients whose treatment was stopped after gallstone dissolution. After starting treatment, the mean biliary cholesterol saturation index (based on criteria of Hegardt and Dam, 1971) decreased from 1-49 +/- SEM 0-17 to 0-92 +/- 0-13 at three weeks and 0-88 +/- 0-10 at four weeks, by which time bile lipid composition had become relatively constant. In patients whose treatment was stopped, bile reverted to its supersaturated state within one week, changing from an on-treatment mean saturation index of 0-74 +/- 0-10 to 1-15 +/- 0-15 in six to eight days after withdrawing CDCA. The proportion of conjugated CDCA in the biliary bile acids increased from 27-9 +/- 2-5% to 60-5 +/- 4-2% within four days and to 80-7 +/- 6-2% by four weeks after starting CDCA. When treatment was stopped, the proportion of CDCA reverted to pretreatment levels by two to three weeks. The saturation index was significantly related (P less than 0-001) to the percent of conjugated CDCA present, such that when the proportion of CDCA exceeded 70%, bile was almost invariably unsaturated. Since the mean time taken for bile to become unsaturated was not shorter than the time taken for bile to revert to its supersaturated state, it seems that intermittent treatment would not be adequate to maintain an unsaturated bile and is, therefore, unlikely to be as effective as continuous treatment in dissolving gallstones.

Adult↗
PubMed1977

Desaturation of bile and cholesterol gallstone dissolution with chenodeoxycholic acid.

The feeding of one of the major biliary bile acids, chenodeoxycholic acid, at a dose of 10 to 15 mg/kg per day causes the circulating bile acid pool to become greatly enriched in this bile acid. When chenodeoxycholic acid composes more than 70% of the biliary bile acids, the amount of cholesterol secreted in bile falls, and bile becomes unsaturated in cholesterol. If cholesterol gallstones are present and are exposed to this unsaturated bile, they will dissolve in 4 to 24 months in the majority of patients. Extensive clinical experience indicates that such medical therapy is safe, despite unequivocal toxicity of chenodeoxycholic acid in several nonhuman primates. When therapy is stopped, bile resaturates, and stones may recur. Since cholecystecomy is a rapid, safe, effective, and usually permanent treatment for all gallstones, the value of medical therapy remains uncertain at present, except for patients in whom surgery is inadvisable. Nonetheless, the demonstration that chenodeoxycholic acid ingestion will desaturate bile and induce gallstone dissolution would appear to be an important pharmacological advance.

Adult↗