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PubMed1976

Bile acids in bile during long-term chenodeoxycholic acid treatment.

Relative concentrations of conjugated and sulfated bile acids in duodenal bile were measured in 5 patients before and during treatment with 0.50-0.75 g of chenodeoxycholic acid per day for 3-4 months. Lithocholic acid constituted 0.8-3.3% (mean 1.8%) of total conjugated and sulfated bile acids before and 0-5.4% (mean 2.6%) during treatment. Lithocholic acid was the predominant bile acid in the sulfate fraction in three patients and chenodeoxycholic acid in two. Sulfated bile acids constituted less than 1% of total bile acids and did not increase during treatment. Ursodeoxycholic acid, the other major metabolite of chenodeoxycholic acid, was found in higher amounts during therapy. The unsaturated bile acid 3beta-hydroxy-delta5-cholenic acid, which was found exclusively as its sulfate ester, showed a slight fall. The average G/T conjugation ratio rose from 2.2 to 4.5.

Bile↗
PubMed1981

Portal blood concentrations of conjugated cholic and chenodeoxycholic acids. Relationships to bile salt synthesis in liver cells.

1. Rats were maintained in a strictly controlled environment of 12 h illumination and 12 h darkness. At regular intervals during the light/dark cycle the portal blood conjugated cholic acid and conjugated chenodeoxycholic acid concentrations were measured. The bile salt concentrations exhibited similar diurnal rhythms, the highest concentrations occurring in the middle of the dark phase. 2. The concentrations of conjugated cholic and chenodeoxycholic acids in the portal blood of rats fed a diet containing the bile salt sequestrant, cholestyramine, were significantly lower than those found in rats given a control diet. 3. During total biliary drainage the portal blood concentrations of conjugated cholic and chenodeoxycholic acids fell to a minimum 6--8 h after the start of the experiment, whereas bile salt synthesis in hepatocytes isolated from the rats was not increased until the least 13 h after the commencement of total biliary drainage. 4. These results suggest that the concentrations of bile salts in the portal blood do not affect directly the diurnal fluctuation in rates of bile salt synthesis, as the response of synthesis to a change in portal blood bile salt concentrations is too slow. 5. When the rats were given a small supplement of cholesterol in the diet to suppress hepatic cholesterologenesis prior to being subjected to total biliary drainage, the changes in the portal blood concentrations of conjugated cholic and chenodeoxycholic acids and the synthesis of the two bile salts by isolated hepatocytes were similar to those found in rats given the control diet. 6. The rise in bile salt production seen during biliary drainage may not be dependent exclusively on a preceding increase in cholesterol synthesis.

Animals↗
PubMed1981

Solvolysis of chenodeoxycholic acid sulfates.

Chemical solvolysis of chenodeoxycholic acid sulfates was studied using 4 published methods. Quantitative recovery of chenodeoxycholic acid from the 3-sulfate was obtained with each method. However, only 2 methods yielded chenodeoxycholic acid after solvolysis of the 7-sulfate. In each instance a compound resembling lithocholic acid by GLC but identifiable as a derivative of chenodeoxycholic acid by mass spectrometry was obtained and represents a product formed during solvolysis. Failure to obtain adequate solvolysis of chenodeoxycholic acid 7-sulfate can lead to false identification of monohydroxy bile acids and apparent absence of th 7-sulfate and disulfate esters.

Chenodeoxycholic Acid↗
PubMed1975

Validation of use of 11,12-2H-labeled chenodeoxycholic acid in isotope dilution measurements of bile acid kinetics in man.

Chenodeoxycholic acid labeled with 2H in the 11 and positions was prepared by catalytic reduction of delta 11-12 unsaturated derivatives of cholic acid. To validate the use of this stable isotope for the determination of bile acid kinetics by isotope dilution, it was administered to seven normal male volunteers simultaneously with [24-14C]chenodeoxycholic acid. Bile was collected at regular intervals over the following 5 days, and the chenodeoxycholic acid pool size and fractional turnover rate were determined from the specific activity decay curve for 14C and from the isotopic abundance curve for 2H. Estimates of the pool size by both isotopes showed a correlation of r = 0.95 and similar precision. Synthesis rate, the product of pool size and fractional turnover rate, also showed good agreement (r = 0.97), Because previous investigations have shown that bile acids tagged with hydrogen isotopes at the 11 and 12 positions are stable in man, the present data suggest that 11, 12-2H-labeled bile acids may be used in place of radioactive isotopes for valid isotopic measurement of bile acid kinetics in healthy infants and children.

Adult↗
PubMed1985

Mass spectrometry identification of biliary bile acids in bile from patients with gallstones before and during treatment with chenodeoxycholic acid. An ancillary study of the National Cooperative Gallstone Study.

The chemical structure of individual bile acids in 255 duodenal bile samples obtained from patients with radiolucent gallstones before and during treatment with chenodeoxycholic acid (375 or 750 mg/day) was determined by coupled gas chromatography/mass spectrometry. The two primary bile acids, cholic acid and chenodeoxycholic acid, and their metabolic products, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, were present in all bile samples and constituted greater than 97% of all bile acids. In pretreatment samples, the 12-oxo derivative of deoxycholic acid (3 alpha-hydroxy-12-oxo-cholanoic acid) was the next most abundant bile acid, being present in 62% of the samples; the average concentration was 1%, but three individuals had 6% to 8% of this bile acid. The 7-oxo derivative of chenodeoxycholic acid was also present in the majority of samples, but at a lower proportion (0.3%); five individuals had 2% to 3%. The 7-oxo derivative of cholic acid was present in a minority of samples (37%) in trace concentrations; isodeoxycholic acid and the 3-oxo derivatives of chenodeoxycholic acid and deoxycholic acid were also present in trace amounts. Four patients had 1% to 11% ursocholic acid in bile. During treatment with chenodeoxycholic acid, bile became enriched in it in direct relation to dosage; the concentration of its bacterial metabolites increased, and the proportion of cholic acid and its bacterial metabolites showed a reciprocal decrease. No unusual bile acids appeared, indicating that treatment with these doses of chenodeoxycholic acid does not result in the occurrence of additional uncommon bile acids in bile. It is suggested that the paucity of uncommon bile acids in bile, which contrasts strikingly with the great variety of uncommon bile acids known to be present in urine and feces, is the result of two factors: (1) the conversion of uncommon bile acids to common bile acids by reduction, hydroxylation, or epimerization during hepatic passage; and (2) efficient hepatic transport of common but not uncommon bile acids into bile.

Bile↗
PubMed1976

[Alterations of bile acid metabolism during treatment with chenodeoxycholic acid. Studies of the role of the appearance of ursodeoxycholic acid in the dissolution of gallstones (author's transl)].

Nine patients with radiolucent stones in the gallbladder were investigated before and during treatment with chenodeoxycholic acid (CDC). During treatment the biliary composition of bile acids changed considerably. Before the ingestion of CDC,bile acids consisted predominantly of cholic acid, deoxycholic acid and CDC; lithocholic acid was present in small amounts only. In the course of treatment CDC or this bile acid together with ursodeoxycholic acid (UDC) became the major biliary bile acid. The content of CDC increased from 47.5 +/- 4.21 to 79.2 +/- 6.37 SEM %, whereas that of UDC increased from 2.7 +/- 1.15 to 13.4 +/- 6.4%. The unsulfated lithocholic acid increased slightly from 0.7 +/- 0.22 to 2.7 +/- 0.41%. The bile acid pool expanded by an average of 130%. The degree of expansion of the pool varied considerably among the different patients. The largest increase in the pool size, however, occurred in the patients with the largest content of UDC in bile. Gallstone dissolution was observed in five patients. Among these five were those patients with the highest content of UDC, Corresponding 8.6, to 29.4 and 51.7%, respectively. These findings suggest that, in addition to CDC, UDC has a cholelitholytic effect in vivo. Of interest also was the observation that the patients in whom the size of the bile acid pool increased only very little showed no dissolution of gallstones. Both the stool weight and the fecal excretion of the isotopes, after the administration of radioactively labeled bile acids, increased only slightly during the treatment with CDC. The cholelitholytically efficacious dose of 20 mg/kg/day of CDC applied in this study appears to be useful in that 94% of it was abosrbed.

Chenodeoxycholic Acid↗
PubMed1980

Chenodeoxycholic acid (CDCA) versus ursodeoxycholic acid (UDCA): a comparison of their effects in pregnant rats.

Treatment of pregnant rats with ursodeoxycholic acid or chenodeoxycholic acid at 3 dose levels resulted in no dismorphogenic effects although embryotoxicity and fatty infiltration in maternal liver were more frequent after CDCA. Light microscopic examination showed no evidence of derangement in fetal liver. Electron microscopic study, carried out in maternal liver, showed that changes were present only in dams treated with the highest doses of both bile acids.

Animals↗
PubMed1983

Comparative efficacy and side effects of ursodeoxycholic and chenodeoxycholic acids in dissolving gallstones. A double-blind controlled study.

In a double-blind controlled study of ursodeoxycholic acid (400 and 800 mg/day) and chenodeoxycholic acid (375 and 750 mg/day), in comparison with placebo, ursodeoxycholic acid was significantly more effective than chenodeoxycholic acid in dissolving gallstones after 12 mo of treatment. Although there continued to be better dissolution during ursodeoxycholic acid treatment (dissolution complete in 30% and partial in another 30% of the patients) than during chenodeoxycholic acid treatment (dissolution complete in 7% and partial in 40%) at 24 mo, this difference between the treatment groups was no longer statistically significant. The incidence of floating stones was significantly higher in the patients who dissolved their stones than in those who did not (p less than 0.001). The three failures of dissolution of floating stones during bile acid treatment were associated with chenodeoxycholic acid therapy--two of them with the 750-mg and the third with the 375-mg doses. Gallstone dissolution with ursodeoxycholic acid occurred in spite of a rise in biliary cholesterol saturation, which was consistent with a nonmicellar mechanism of cholelitholysis. Furthermore, more than threefold serum elevations of L-alanine aminotransferase were observed only during chenodeoxycholic acid therapy. They occurred in 2 patients treated with 375 and 750 mg/day, respectively. The enzyme levels normalized after discontinuation of chenodeoxycholic acid and have remained normal for 13 and 8 mo, respectively, after the institution of treatment with 800 mg/day of ursodeoxycholic acid. There was no correlation between the liver tests and biliary levels of lithocholic acid. Of all the symptoms studied, only constipation showed changes that approached statistical significance (p = 0.0681). There was a significant improvement of constipation in the combined chenodeoxycholic acid groups when they were compared with the combined ursodeoxycholic acid groups. The total bile acid pool expanded significantly in both the chenodeoxycholic acid and in the 800-mg ursodeoxycholic acid treatment groups. The marked increases of biliary ursodeoxycholic acid and chenodeoxycholic acid, respectively, indicated compliance with the treatment in all but 1 bile acid-treated patient. Neither serum triglycerides nor serum cholesterol showed significant changes in any of the treatment groups. The study shows that ursodeoxycholic acid dissolves gallstones faster and with fewer side effects than chenodeoxycholic acid. The results of the study are also consistent with the view that ursodeoxycholic acid is cholelitholytic at a lower dose than is chenodeoxycholic acid.

Alanine Transaminase↗
PubMed1985

In vivo and vitro studies on formation of bile acids in patients with Zellweger syndrome. Evidence that peroxisomes are of importance in the normal biosynthesis of both cholic and chenodeoxycholic acid.

The last step in bile acid formation involves conversion of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA) into cholic acid and 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid (DHCA) into chenodeoxycholic acid. The peroxisomal fraction of rat and human liver has the highest capacity to catalyze these reactions. Infants with Zellweger syndrome lack liver peroxisomes, and accumulate 5 beta-cholestanoic acids in bile and serum. We recently showed that such an infant had reduced capacity to convert a cholic acid precursor, 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol into cholic acid. 7 alpha-Hydroxy-4-cholesten-3-one is a common precursor for both cholic acid and chenodeoxycholic acid. Intravenous administration of [3H]7 alpha-hydroxy-4-cholesten-3-one to an infant with Zellweger syndrome led to a rapid incorporation of 3H into biliary THCA but only 10% of 3H was incorporated into cholic acid after 48 h. The incorporation of 3H into DHCA was only 25% of that into THCA and the incorporation into chenodeoxycholic acid approximately 50% of that in cholic acid. The conversion of intravenously administered [3H]THCA into cholic acid in another infant with Zellweger syndrome was only 7%. There was a slow conversion of THCA into 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-C29-dicarboxylic acid. The pool size of both cholic- and chenodeoxycholic acid was markedly reduced. Preparations of liver from two patients with Zellweger syndrome had no capacity to catalyze conversion of THCA into cholic acid. There was, however, a small conversion of DHCA into chenodeoxycholic acid and into THCA. It is concluded that liver peroxisomes are important both for the conversion of THCA into cholic acid and DHCA into chenodeoxycholic acid.

Bile Acids and Salts↗
PubMed1983

Measurement of bile acid kinetics in human serum using stable isotope labeled chenodeoxycholic acid and capillary gas chromatography electron impact mass spectrometry.

A non invasive method for measurement of bile acid kinetics in serum using (24-13C)chenodeoxycholic acid has been developed. After oral administration of 50 mg (24-13C)chenodeoxycholic acid, the exponential decay of the 13C atom percent excess was measured in serum using capillary gas chromatography mass spectrometry. This required that isotope ratios were measured with high accuracy and coefficients of variation less than 1% by means of selected ion monitoring and scan averaging. The clinical applicability was tested by repeated determination of pool size, fractional turnover and synthesis rate of chenodeoxycholic acid in one healthy volunteer. This method permitted the determination of pool size, synthesis and conversion of chenodeoxycholic acid into lithocholic acid in man without the use of radioactive tracers and without repeated duodenal intubation.

Bile Acids and Salts↗
PubMed1985

Isolation and identification of delta 6-lithocholenic acid (3 alpha-hydroxy-5 beta-6-cholen-24-oic acid) as an intestinal bacterial metabolite of chenodeoxycholic acid in man.

Fecal bacterial biotransformation studies of chenodeoxycholic acid were performed. Incubations were carried out for 30-s to 12-h time intervals. delta 6-Lithocholenic acid was isolated by thin-layer chromatography. Its structure was confirmed by gas-liquid chromatography and mass spectrometry. The proportion of chenodeoxycholic acid biotransformed to delta 6-lithocholenic acid consistently ranged from 5.5 to 14.0%.

Aerobiosis↗
PubMed1994

Comparative studies of metabolism of simultaneously administered chenodeoxycholic acid and ursodeoxycholic acid in hamsters.

We present the comparative studies of metabolism of chenodeoxycholic acid and ursodeoxycholic acid and their taurine conjugates in the liver and fecal culture from hamsters. When [24-14C]chenodeoxycholic acid and [11,12-3H]ursodeoxycholic acid were simultaneously instilled into the jujunal loop of bile fistula hamsters, both bile acids administered were recovered mainly as their conjugates with taurine and glycine in the fistula bile. The recovery of chenodeoxycholic acid was slightly but significantly higher than that of ursodeoxycholic acid. Chenodeoxycholic acid was more efficiently conjugated with glycine than ursodeoxycholic acid. The glycine/taurine ratio in the biliary chenodeoxycholic acid was 1.9, and that in ursodeoxycholic acid was 1.6. In addition, as much as 6.2% of ursodeoxycholic acid was excreted as the unconjugated form; on the other hand only 2.4% of unconjugated chenodeoxycholic acid was excreted. When [24-14C]chenodeoxycholyltaurine and [11,12-3H]ursodeoxycholyltaurine were simultaneously administered into the ileum loop of bile fistula hamsters, both bile salts were absorbed and secreted efficiently into the bile at the same rate. These results indicate that slightly lower recovery of ursodeoxycholic acid in the bile could be due to the less effective conjugation of ursodeoxycholic acid than chenodeoxycholic acid in the liver. Deconjugation by fecal culture from a hamster proceeded more rapidly in chenodeoxycholyltaurine than ursodeoxycholyltaurine. 7-Dehyroxylation to form lithocholic acid by fecal culture was also faster in chenodeoxycholic acid than ursodeoxycholic acid. The formation of 7-oxolithocholic acid from ursodeoxycholic acid was lesser than from chenodeoxycholic acid. In summary, bacterial deconjugation followed by 7-dehydroxylation to form lithocholic acid seems to be achieved more efficiently with chenodeoxycholic acid than ursodeoxycholic acid.

Animals↗
PubMed1976

Hepatic morphology and bile acid composition of bile and urine during chenodeoxycholic acid therapy for radiolucent gallstones.

In 9 patients with radiolucent gallstones, percutanous liver biopsy was performed during treatment with chenodeoxycholic acid in a dose of 500 to 750 mg per day for 3-14 months. In 4 patients pretreatment specimens were available for comparison. No sign of hepatic cellular necrosis or bile duct proliferation was noticed in the biopsies. In 2 patients hepatic steatosis was reduced, and in one patient moderate portal tract inflammation decreased during therapy. Mean values of alkaline phosphatases, alanine aminotransferases, prothrombin, and serum lipids remained unchanged and did not exceed normal limits. In 5 patients the urinary bile acid profile was examined during therapy. Chenodeoxycholic acid constituted 27-50%, lithocholic acid 25-63%, and ursodeoxycholic acid 0-13% of total bile acids in urine. The renal excretion of total bile acids was estimated to be less than two mg per day in each patient. From 86 to 100 per cent of the bile acids in urine was sulfated.

Bile↗
PubMed1977

Feasibility of low-dose and intermittent chenodeoxycholic acid therapy of gallstones.

Chenodeoxycholic acid, by reducing the concentration of biliary cholesterol relative to that of bile acid and phospholipid, dissolves cholesterol gallstones. This bile acid, however, has potential dose-related hepatotoxicity and causes dose-related diarrhea. Therefore, the feasibility of low-dose and intermittent therapy was assessed by studying the induction and persistence of chenodeoxycholic acid-induced biliary lipid changes. Biliary lipid composition with each of 3 doses of chenodeoxycholic acid was determined in bile samples obtained by cholecystokinin-stimulated duodenal drainage before, after one week and one month of treatment, and up to 9 weeks after discontinuation of treatment. The lowest dose that significantly reduced the relative concentration of biliary cholesterol was 250 mg/day. A significant reduction occurred one week after initiation of treatment and was maintained for 9 weeks following discontinuation of treatment. Thus, clinical trials on low-dose and intermittent chenodeoxycholic acid therapy for gallstone prophylaxis or dissolution are warranted.

Adult↗