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PubMed1990

Potential bile acid precursors in plasma--possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man.

The plasma concentrations of 3 beta-hydroxy-5-cholestenoic acid, 3 beta,7 alpha-dihydroxy-5-cholestenoic acid and 7 alpha-hydroxy-3-oxo-4-cholestenoic acid have been compared with that of 7 alpha-hydroxy-4-cholesten-3-one in healthy subjects and in patients with an expected decrease or increase of the bile acid production. In controls and patients with liver disease, the level of 7 alpha-hydroxy-3-oxo-4-cholestenoic acid was positively correlated to that of 3 beta,7 alpha-dihydroxy-5-cholestenoic acid and not to that of 7 alpha-hydroxy-4-cholesten-3-one. In patients with stimulated bile acid formation the levels of the acids were not correlated to each other but there was a significant positive correlation between the levels of 7 alpha-hydroxy-3-oxo-4-cholestenoic acid and 7 alpha-hydroxy-4-cholesten-3-one. These findings indicate that the precursor of 7 alpha-hydroxy-3-oxo-4-cholestenoic acid differs depending on the activity of cholesterol 7 alpha-hydroxylase. Since the activity of this enzyme is reflected by the level of 7 alpha-hydroxy-4-cholesten-3-one in plasma the findings are compatible with a formation of 7 alpha-hydroxy-3-oxo-4-cholestenoic acid from 3 beta,7 alpha-dihydroxy-5-cholestenoic acid when the rate of bile acid formation is normal or reduced and from 7 alpha-hydroxy-4-cholesten-3-one under conditions of increased bile acid synthesis. In support of this interpretation, 7 alpha,26-dihydroxy-4-cholesten-3-one was identified at elevated levels in plasma from patients with ileal resection or treated with cholestyramine. The levels of 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one were also higher than normal in these patients. Based on these findings and previous knowledge, a model is proposed for the biosynthesis of bile acids in man. Under normal conditions, two major pathways, one "neutral" and one "acidic" or "26-oxygenated", lead to the formation of cholic acid and chenodeoxycholic acid, respectively. These pathways are separately regulated. When the activity of cholesterol 7 alpha-hydroxylase is high, the "neutral" pathway is most important whereas the reverse is true when cholesterol 7 alpha-hydroxylase activity is low. In cases with enhanced activity of cholesterol 7 alpha-hydroxylase, the "neutral" pathway is connected to the "acidic" pathway via 7 alpha,26-dihydroxy-4-cholesten-3-one, whereas a flow from the acidic pathway to cholic acid appears to be of minor importance.

Adult↗
PubMed1985

Metabolism of lithocholic and chenodeoxycholic acids in the squirrel monkey.

Metabolism of lithocholic acid (LCA) and chenodeoxycholic acid (CDCA) was studied in the squirrel monkey to clarify the mechanism of the lack of toxicity of CDCA in this animal. Radioactive LCA was administered to squirrel monkeys with biliary fistula. Most radioactivity was excreted in the bile in the form of unsulfated lithocholyltaurine. The squirrel monkey thus differs from humans and chimpanzees, which efficiently sulfate LCA, and is similar to the rhesus monkey and baboon in that LCA is poorly sulfated. When labeled CDCA was orally administered to squirrel monkeys, less than 20% of the dosed radioactivity was recovered as LCA and its further metabolites in feces over 3 days, indicating that bacterial metabolism of CDCA into LCA is strikingly less than in other animals and in humans. It therefore appears that LCA, known as a hepatotoxic secondary bile acid, is not accumulated in the squirrel monkey, not because of its rapid turnover through sulfation, but because of the low order of its production.

Animals↗
PubMed1985

Serum bile acid determination after different doses of orally ingested chenodeoxycholic acid. Evaluation of a simplified enzymatic method.

A simplified enzymatic method for determination of serum 3 alpha-hydroxy bile acids (3 alpha-HBA) has been evaluated. Analytical precision was low in the normal range but satisfactory for elevated values. The fasting upper reference value was 8.0 mumol/l. In 12 healthy subjects serum 3 alpha-HBA levels were measured after oral loads (125, 250, 500, and 1000 mg) of unconjugated chenodeoxycholic acid (CDA). After the 125-mg CDA loading dose no significant increase in serum 3 alpha-HBA was observed, but with the 250 mg CDA loading dose serum 3 alpha-HBA levels were elevated at 30, 60, and 120 min. The loading doses of 500 mg and 1000 mg CDA produced significant increases in serum 3 alpha-HBA levels throughout the observation period (3 h). When sera with increased serum bile acids were analyzed by radioimmunoassay for CDA, the results correlated well with those obtained enzymatically. The usefulness of the simplified method is evident in this situation, and we also find it useful for serum bile acid determination after an oral bile acid loading test with CDA. The method is easy to perform and requires only standard laboratory equipment.

Administration, Oral↗
PubMed1979

Metabolism of potential precursors of chenodeoxycholic acid in cerebrotendinous xanthomatosis (CTX).

In patients with cerebrotendinous xanthomatosis (CTX), diminished cholic acid production is associated with incomplete oxidation of the cholesterol side chain and the excretion of C(25)-hydroxy bile alcohols. The aims of this investigation were 1) to provide quantitative information on the pool size and production rate of chenodeoxycholic acid by the isotope dilution technique; and 2) to investigate the possible existence of a block in chenodeoxycholic acid synthesis and explain the absence of chenodeoxycholic acid precursors in CTX. After the injection of [24-(14)C]chenodeoxycholic acid, measurements of chenodeoxycholic acid pool size and production rate in a CTX subject were, respectively, 1/20 and 1/6 as great as controls. Further, three potential precursors of chenodeoxycholic acid, namely [G-(3)H]7alpha-hydroxy-4-cholesten-3-one, [G-(3)H]5beta-cholestane-3alpha,7alpha,25-triol, and [G-(3)H]5beta-cholestane-3alpha,7alpha,26-triol, were administered to the CTX and control subjects and the specific activity curves of [G-(3)H]cholic acid and [G-(3)H]chenodeoxycholic acid were constructed and compared. In the control subjects, the two bile acids decayed exponentially, but in the CTX patient maximum specific activities were abnormally delayed, indicating the hindered transformation of precursor into bile acid. These results show that chenodeoxycholic acid synthesis is small in CTX and that the conversion of 7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestane-3alpha,7alpha,25-triol, and 5beta-cholestane-3alpha,7alpha,26-triol to both chenodeoxycholic acid and cholic acid were similarly impaired.

Adult↗
PubMed1986

Transformation of chenodeoxycholic acid to ursodeoxycholic acid in patients with Crohn's disease.

In vivo 7 beta-epimerization of chenodeoxycholic acid to ursodeoxycholic acid and the role of 7-ketolithocholic acid as an intermediate in this biotransformation were studied in 11 patients with Crohn's disease and in 5 healthy volunteers. The incorporation of deuterium into biliary ursodeoxycholic acid and 7-ketolithocholic acid was determined by computed gas chromatography-mass fragmentography after ingestion of a dideuterated chenodeoxycholic acid, chenodeoxycholic-11,12-d2 acid. The incorporation of deuterium into ursodeoxycholic acid increased to a peak level at 48 h in the patients with Crohn's disease, but was delayed in healthy volunteers. In 8 patients and 2 healthy controls there were small amounts of 7-ketolithocholic acid in bile. The incorporation of deuterium into 7-ketolithocholic acid was confirmed in only 2 patients and the peak level was noted at 48 h. These observations suggest that 7-ketolithocholic acid is an intermediate of this biotransformation in patients with Crohn's disease.

Adolescent↗
PubMed1981

Cerebrotendinous xanthomatosis: defective liver mitochondrial hydroxylation of chenodeoxycholic acid precursors.

Oxidation of the side chain of 5 beta-cholestane-3 alpha, 7 alpha-diol, 7 alpha-hydroxy-4-cholesten-3-one, and 5-cholestene-3 beta, 7 alpha-diol has been studied in subcellular fractions of liver from a patient with cerebrotendinous xanthomatosis (CTX) and a control subject. All intermediates were efficiently 26-hydroxylated and further converted to the corresponding 26-carboxylated derivatives by the mitochondrial fraction of normal human liver. No such conversion was observed with the mitochondria from the liver of the CTX patient and the control subject. 12 alpha-Hydroxylation of the patient and the control subject. 12 alpha-Hydroxylation of the substrates was very efficient with the microsomal fractions from both subjects. Bases on these and previous findings (Oftebro, H., I. Björkhem, S. Skrede, A. Schreiner, and J. I. Pedersen. 1980. J. Clin. Invest. 65: 1481-1430), it i concluded that the metabolic defect in CTX is a complete lack of mitochondrial C27-steroid 26-hydroxylase. In CTX the precursors of chenodeoxycholic acid are first attacked by the microsomal 12 alpha-hydroxylase and subsequently by the microsomal 25-hydroxylase as an alternate route to cholic acid formation. This explains the increased ratio of cholic acid to chenodeoxycholic acid observed in the bile of these patients. In the normal liver the formation of both cholic acid and chenodeoxycholic acid involves a mitochondrial 26-hydroxylation.

Adult↗
PubMed1978

The hypotriglyceridemic effect of chenodeoxycholic acid in type IV hyperlipemia.

The effect of chenodeoxycholic acid on the fasting serum triglycerides was studied in 30 patients with type IV hyperlipemia and in 20 patients with primary gout and associated endogenous hypertriglyceridemia, the triglycerides being determined before treatment and at monthly intervals for three months. Chenodeoxycholic acid treatment resulted in a significant lowering of the serum triglycerides in both groups of patients. The drug was well tolerated and there were no undesirable side-effects. Although the mechanism of action is still not known, the drug is thought to reduce triglyceride synthesis in the liver. Chenodeoxycholic acid appears to be electively indicated in type IV hyperlipemia treatment.

Adult↗
PubMed1981

Effects of feeding chenodeoxycholic acid on metabolism of cholesterol and bile acids in germ-free rats.

The aim of this investigation was to study the influence of chenodeoxycholic acid administration on cholesterol and bile acid synthesis in germ-free rats. Seven rats were fed a basal diet and 2 groups of 4 rats received the same diet supplemented with 0.4 and 1% chenodeoxycholic acid, respectively. After 6 weeks, feces were collected in one 3- and one 4-day pool for analysis of cholesterol and bile acids. When the sampling period was finished, the rats were killed and the liver microsomal fractions isolated. The activities of HMG CoA reductase and cholesterol 7 alpha-hydroxylase were determined, the 7 alpha-hydroxylase by a mass fragmentographic method. The 2 dominating bile acids in the untreated rats were cholic acid and beta-muricholic acid. During treatment with chenodeoxycholic acid, 60--70% of this bile acid was converted into alpha- and beta-muricholic acid, indicating a high activity of the 6 beta-hydroxylase. The excretion of cholic acid was almost completely inhibited and the 7 alpha-hydroxylase activity was decreased ca 75% in the rats fed 1% chenodeoxycholic acid. The activity of the hepatic HMG CoA reductase as unchanged. The fecal excretion of cholesterol increased 2--3 times. An accumulation of cholesterol was seen in the rats treated with 1% chenodeoxycholic acid, which was probably a result of the decreased catabolism of cholesterol to bile acids.

Animals↗
PubMed1985

Serum bile acids in Gilbert's syndrome after oral load of chenodeoxycholic acid.

Oral bile acid loading tests using 1 g of unconjugated chenodeoxycholic acid (CDA) were performed in subjects with Gilbert's syndrome before and after reduced caloric intake. The study was carried out to ascertain whether the hepatic handling of CDA was restricted in the same manner as recently described for ursodeoxycholic acid. In subjects with Gilbert's syndrome, the bile acid concentrations after the oral loading tests did not differ significantly from those found in reference groups. No differences were found in the serum bile acid values before and after caloric restriction, indicating that the bile acid handling was not influenced by the increased bilirubin levels obtained after fasting. Our results indicate that the hepatic handling of CDA is normal in Gilbert's syndrome.

Administration, Oral↗
PubMed1978

Effect of chenodeoxycholic acid on serum and biliary lipids in patients with hyperlipoproteinaemia.

1. In order to study the effects of chenodeoxycholic acid on serum and biliary lipids in hyperlipoproteinaemia, chenodeoxycholic acid was administered to seven type IIa, eight type IIb and eight type IV patients in a daily dose of 750 mg (1.9 mmol) for 3 months. 2. The serum concentrations of cholesterol and triglycerides were determined at 4-week intervals: cholesterol remained unchanged whereas triglycerides decreased 15--20%. 3. In 17 patients, biliary lipids were studied. The proportion of chenodeoxycholic acid in the bile increased to about 70%; lithocholic acid and ursodeoxycholic acid increased significantly. 4. Bile saturation with cholesterol decreased and correlated negatively with the proportion of chenodeoxycholic acid in biliary bile acids but positively with serum triglycerides. 5. It is concluded that chenodeoxycholic acid treatment in hyperlipoproteinaemia is associated with parallel fall in serum triglycerides and biliary cholesterol and thus may prove to be a useful adjunct in hypolipidaemic treatment.

Bile↗
PubMed1979

Transformation of chenodeoxycholic acid and ursodeoxycholic acid by human intestinal bacteria.

Feces from normal subjects and patients with cerebrotendinous xanthomatosis were incubated anaerobically with labeled chenodeoxycholic acid and ursodeoxycholine acid for known periods, and the bile acids formed were analyzed by TLC and scintillation counting. In the normal subjects, 80% of the chenodeoxycholic acid and 41% of the ursodeoxycholic acid were 7-dehydroxylated to lithocholic acid during 2 hr of incubation. In contrast, the fecal flora of the CTX patients transformed only 5% of chenodeoxycholic acid and less than 1% of ursodeoxycholic acid to lithocholic acid during the same time period. In several subjects (normals and CTX), the intestinal flora converted chenodeoxycholic acid to ursodeoxycholic acid without the accumulation of the hypothetical intermediate 7-ketolithocholic acid (3 alpha-hydroxy-7-keto-5 beta-cholanoic acid). These results indicate that the fecal bacterial flora is capable of 7-dehydroxylating chenodeoxycholic acid and ursodeoxycholic acid to yield lithocholic acid. Apparently the enzymes involved are relatively stereospecific since the 7 beta-hydroxy group of ursodeoxycholic acid was removed more slowly than the 7 alpha-hydroxy group of chenodeoxycholic acid.

Adult↗
PubMed1979

Chronic administration of chenodeoxycholic acid increases cholesterol saturation in bile in the dog.

Six dogs were given chenodeoxycholic acid, 200 mg/day for 15 days; gallbladder and hepatic bile samples were taken and biliary bile acids, phospholipids and cholesterol were compared to those of fourteen control dogs. It was found that: (1) the cholesterol saturation index of gallbladder bile was higher in treated dogs (0.12 +/- 0.06; m +/- SD) than in controls (0.07 +/- 0.01; P less than 0.05); the proportion of chenodeoxycholic acid in gallbladder bile was higher in treated dogs (27.8 +/- 12.5%) than in controls (4.5 +/- 1.9%; P less than 0.01); (2) in hepatic bile, the saturation index and proportion of chenodeoxycholic acid were significantly higher in treated dogs (respectively 0.13 +/- 0.03 and 21.6 +/- 8.8%) than in control dogs (respectively 0.07 +/- 0.01; P less than 0.01 and 4.6 +/- 2.2%; P less than 0.01). In the dog, chronic administration of chenodeoxycholic acid increases cholesterol saturation in bile. It is concluded that the difference of effect of chenodeoxycholic acid in man and in the dog is not related to the duration of administration, but to a species difference.

Administration, Oral↗
PubMed1973

Serum lipids in cholelithiasis: effect of chenodeoxycholic acid therapy.

Hypercholesterolaemia has been predicted as a possible complication of chenodeoxycholic acid treatment for gall stones. To exclude this, fasting serum lipids were measured in patients with stones before and at monthly intervals for six months after starting chenodeoxycholic acid. Before treatment half of a group of 36 patients with presumed cholesterol gall stones had serum cholesterol levels exceeding 260 mg/100 ml or serum triglyceride values greater than 160 mg/100 ml or both; these lipid levels were significantly greater than those in control subjects matched for age and sex. Treatment with chenodeoxycholic acid (0.5-1.5 g/day by mouth) did not change serum cholesterol levels but did significantly reduce serum triglyceride concentrations from a pretreatment level of 118 (+/- S.E. of mean 11.7) mg/100 ml to 95 (+/- 7.2) mg/100 ml after six months of therapy. The mechanism of this triglyceride-lowering action of chenodeoxycholic acid is not known, but it may have therapeutic value in patients with hypertriglyceridaemia.

Adult↗
PubMed1976

Bile acid glucuronides, II[1]. Isolation and identification of a chenodeoxycholic acid glucuronide from human plasma in intrahepatic cholestasis.

The isolation of a glucurono-conjugate of a bile acid has been performed from human plasma in a case of chronic intrahepatic cholestasis. By means of a series of chromatographic steps, esterification with diazomethane and acetylation a mixture of methylester polyacetates of steroid glucuronides was obtained, which could be separated by thin-layer chromatography. Methyl 7alpha-acetoxy-3alpha-O-(methyl 2, 3, 4-tri-O-acetyl-beta-D-glucopyranosyluronate)5beta-cholan-24-oate, synthesized via the Koenigs-Knorr condensation reaction, was used as reference substance. From comparison of the chromatogrphic behaviour and the mass spectrum of the natural compound and the synthetic product the structure of the bile acid derivative isolated from plasma could be established as a peracetylated methylester of chenodeoxycholic acid-3-beta-D-glucuronide.

Bile Acids and Salts↗
PubMed1976

Effect of type of dietary fat, cholesterol and chenodeoxycholic acid on gallstone formation, bile acid kinetics and plasma lipids in squirrel monkeys.

To explore the effect of type of dietary fat, cholesterol and chenodeoxycholic acid on gallstone formation, bile formation, bile composition, bile acid kinetics and plasma lipids in squirrel monkeys, 39 monkeys were studied using seven different diets. Safflower oil, a highly unsaturated fat, added to a diet with cholesterol resulted in at least as high an incidence of cholesterol gallstones as butter added to the same diet. On the other hand, diets with high levels of saturated or unsaturated fat without cholesterol did not result in gallstone formation. Dietary chenodeoxycholic acid (0.1%) did not reduce the incidence of cholesterol gallstones, although the proportion of bile acids as chenodeoxycholic acid increased. Gallbladder biles from monkeys fed semipurified diets with cholesterol had a significantly higher lithogenic index than the comparable groups without cholesterol. Pool sizes of bile acids in all semipurified diet groups were reduced and the lithogenic indices were increased compared with the group fed a commercial feed. Dietary chenodeoxycholic acid caused a decrease in plasma cholesterol in butter groups and an increase in triglyceride concentrations in safflower groups. Diet infuences bile composition and bile acid kinetics, as well as the incidence of gallstones, in squirrel monkeys.

Animals↗