Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid.

Bile acid composition in fasting duodenal bile was assessed at entry and at 2 years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10-12 mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high-pressure liquid chromatography method that had been validated against gas chromatography. Percent composition in bile (mean +/- SD) for 98 patients at entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 +/- 18.6, 31.5 +/- 15.5, 8.0 +/- 9.3, 0.3 +/- 1.0, and 0.6 +/- 0.9. Values for CA were increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when compared with values in normal persons. Bile acid composition of the major bile acids did not change after 2 years on placebo medication. By contrast, in patients receiving UDCA for 2 years, bile became enriched with UDCA on average to 40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to 19.5%). No change in percent composition was observed for DCA and LCA. Percent composition at entry and changes in composition after 2 years on UDCA were similar in patients with varying severity of PBC. In patients whose bile was not enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the small amount of UDCA found in some of these specimens were conjugated to a greater extent with glycine (52%-64%) than with taurine (36%-48%). Treatment with UDCA caused the proportion of all endogenous bile acids conjugated with glycine to increase to 69% to 78%, while the proportion conjugated with taurine (22%-31%) fell (P <.05). Administered UDCA was also conjugated predominantly with glycine (87%).     

Changes in bile acid composition and effect on cytolytic activity of fecal water by ursodeoxycholic acid administration: a placebo-controlled cross-over intervention trial in healthy volunteers

BACKGROUND: Ursodeoxycholic acid (UDCA) has been shown to affect membrane-damaging effects of bile acids in vitro and fecal bile acid composition in rats. This study evaluates the effect of UDCA on fecal bile acid composition and on cytolytic activity of fecal water in man to clarify the potential chemopreventive role of UDCA for colorectal cancer. METHODS: In this placebo-controlled crossover intervention trial, the effect of 900 mg/day UDCA orally in 15 healthy volunteers was studied. At the end of each 4-week period, 72 h feces were collected. Total and individual bile acids in feces were determined by gas chromatography and soluble bile acids were analyzed by high-performance liquid chromatography. Cytolytic activity of fecal water was measured using an erythrocyte lysis assay. RESULTS: In feces, the percentages of primary bile acids-cholic acid (CA) and chenodeoxycholic acid (CDCA)-and of secondary bile acid-deoxycholic acid (DCA) - decreased after supplementation with UDCA, whereas those of UDCA and LCA increased from 2.7 +/- 0.4% to 23.7 +/- 2.6%, P < 0.0001 and from 26.2 +/- 1.2% to 49.4 +/- 1.8%, P < 0.0001 respectively. The concentrations of these two bile acids in fecal water also increased after UDCA administration from 7.8 +/- 1.9 micromol/l to 47.0 +/- 6.7 micromol/l (UDCA), P < 0.0001 and from 2.5 +/- 0.6 micromol/l to 18.3 +/- 4.1 micromol/l (LCA), P < 0.002, respectively. Cytolytic activity of fecal water was not affected by UDCA. CONCLUSION: These results do not support a protective effect of UDCA supplementation against colorectal cancer in man.     

Intestinal absorption of ursodeoxycholic acid in patients with extrahepatic biliary obstruction and bile drainage.

Ursodeoxycholic acid (UDCA) dissolves cholesterol gallstones and improves liver function test results in patients with cholestatic liver diseases. Its absorption was studied in patients who had complete extrahepatic biliary obstruction caused by pancreatic carcinoma but no intestinal or liver disease. Six patients received 500 mg chenodeoxycholic acid (CDCA) or 250-2000 mg UDCA in capsules in single oral doses in random order, with an interval of 2 days between the different treatment regimens. In the control period the patients excreted into bile 382.3 +/- 108.0 mumol CDCA (mean +/- SD) and 1866.7 +/- 172.6 mumol cholic acid per 24 hours. After administration of 1273.6 mumol (500 mg) CDCA, biliary excretion of this bile acid increased to 1370.9 +/- 185.7 mumol/24 h, indicating an intestinal absorption rate of 77.6% +/- 9.8%. After oral administration of 636.8 mumol (250 mg), 1273.6 mumol (500 mg), 2547.2 mumol (1000 mg), and 5094.4 mumol (2000 mg) of UDCA, the respective absorption rates were 60.3% +/- 7.4%, 47.7% +/- 9.0%, 30.7% +/- 7.5%, and 20.8% +/- 3.9%, and whereas in the control period no UDCA was detected in the bile, the UDCA percentages measured were 14.6% +/- 8.2%, 19.6% +/- 9.1%, 23.1% +/- 11.3%, and 27.4% +/- 12.1%. The coadministration of CDCA did not enhance the absorption of UDCA. The data indicate that absorption of orally administered CDCA is almost complete, whereas UDCA absorption is incomplete. With increasing doses UDCA absorption decreases. To achieve absorption of adequate amounts of UDCA, high and/or multiple doses are needed.     

Effect of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis C virus infection

Aim:  Many reports have revealed ursodeoxycholic acid (UDCA) to be effective against chronic hepatitis C virus (HCV). However, some cases resist this therapy and the mechanism of action remains unclear. In this study, UDCA was administered to patients with chronic HCV and the correlation between the bile acids of the biliary bile and serum and the drug efficacy was investigated.
Methods:  Fifteen patients were given 600 mg/day of UDCA for more than 24 weeks. The serum bile acid concentrations and biliary and serum bile acid were collected before and after 24 weeks of UDCA treatment, and composition determined by high-performance liquid chromatography.
Results:  The treatment was effective in nine cases (ALT decreased to less than twice the normal values 80 IU/L) and ineffective in six cases. There was no significant difference in the serum bile acid concentrations before and after UDCA treatment between the values of both cases. After UDCA treatment, the serum percentage of UDCA (effective, 62.5 ± 2.0; ineffective, 53.5 ± 2.5, ( P  = 0.02)) and the percentage of chenodeoxycholic acid (CDCA) showed no remarkable changes. In the biliary bile the percentage of CDCA (effective, 30.9 ± 2.0; ineffective, 20.0 ± 3.0, ( P  = 0.007)) and the percentage of UDCA showed no remarkable changes.
Conclusion:  In the effective cases, the percentage of UDCA in the serum and the percentage of CDCA in biliary bile were significantly higher than in the ineffective cases. This indicates that, when effective, CDCA decreases in hepatocytes and this reduction contributes to hepatoprotection.     

Comparison of effects of chenodeoxycholic and ursodeoxycholic acid and their combination on biliary lipids in obese patients with gallstones.

To study the effects of different bile acids on biliary lipids in obese patients with radiolucent gallstones, 12 subjects were given chenodeoxycholic acid (CDCA) at a dose of 15 mg/kg/day, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day, and an equimolar combination of the two (7.5 + 7.5 mg/kg/day) in accordance with a double-blind crossover design. Mean molar percentage of cholesterol and cholesterol saturation index corrected for urso-rich bile (CSI) decreased significantly with all three treatments, but the combination was more effective in decreasing the CSI than either of the two bile acids given alone (p less than 0.05). Bile became desaturated in 10 of 12 patients receiving the combination, in 4 of 12 receiving CDCA, and 3 of 12 receiving UDCA alone. Combination treatment was well tolerated since mild diarrhea and slight increase in transaminases were observed only in a few patients. We conclude that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for dissolution of gallstones in obese patients.     

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (+/- 20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high-dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10-13 mg/kg/d (n = 18) biliary UDCA represented 43.1% + 0.3% (mean + SD) of total bile acids; at a UDCA dose of 14-17 mg/kg (n = 14), its biliary content increased to 46.9% + 0.3%, at 18-21 mg/kg (n = 34) to 55.9% + 0.2%, at 22-25 mg/kg (n = 12) to 58.6% + 2.3%, and at 26-32 mg/kg (n = 8) to 57.7% + 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22-25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22-25 mg/kg may be more effective than lower doses.     

Bile acids influence hepatic chemiluminescence in normal and oxidative-stressed rats†

The aim of the present study was to clarify whether bile acids influence chemiluminescence (CL) in the liver in vivo. Hepatic CL was determined on the surface of the liver of anaesthetized rats by using a photon counter. In normal rats, hepatic CL was significantly decreased 30 min after enteral administration of chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA), but returned to its initial level 3 h later, after part of the CDCA administered was metabolized. Ursodeoxycholic acid (UDCA) and cholic acid had no effect on CL. In contrast, hepatic CL was markedly increased 30 min after CDCA or DCA administration in rats given either buthionine sulphoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase, or diethyldithiocarbamate (DDC), an inhibitor of both superoxide dismutase and glutathione peroxidase. Chenodeoxycholic acid further increased the CL of BSO- or DDC-treated rats during inhalation of oxygen via a tracheal cannula. Coadministration of UDCA eliminated the effects of CDCA on the hepatic CL of normal and BSO- or DDC-treated rats with or without oxygen inhalation. We conclude that cytotoxic bile acids, such as CDCA, increase CL in the antioxidants-depleted or oxidative-stressed liver in vivc, but that UDCA prevents CDCA from developing CL.     

Ursodeoxycholic Acid Suppresses Extent of Lipid Peroxidation in Diseased Liver in Experimental Cholestatic Liver Disease

The therapeutic benefit of ursodeoxycholic acid (UDCA) in treating cholestatic liver disease is globally recognized. It is generally accepted that the mechanism of action of UDCA can be attributed to several diverse processes that appear to be uniformly targeted towards minimizing the deleterious actions of accumulated hydrophobic bile acids in the cholestatic liver. Since hydrophobic bile acids are prooxidants, emerging in vitro evidence suggests that UDCA may have an antioxidant mechanism of action. We hypothesize that UDCA suppresses the extent of lipid peroxidation in the cholestatic liver. This hypothesis was tested by assessing the extent of lipid peroxidation in livers harvested from chronic bile duct ligated (CBDL) rats dosed daily for 24 days with 5, 10, or 15 mg/kg UDCA. The extent of lipid peroxidation was evaluated by determining the hepatic content of conjugated dienes, lipid peroxides, and malondialdehyde. The data were compared with identical data collected from unoperated control and 24-day bile duct manipulated (SO) rats. In the two groups of control rats, UDCA has no effect on the serum indices of liver function. In CBDL rats, UDCA suppressed the increased extent of lipid peroxidation in the liver in a dose-dependent manner in the absence of improvement of laboratory parameters of liver function and hepatic architecture. In conclusion, UDCA suppresses the augmented extent of lipid peroxidation in the diseased liver of CBDL rats.     

The influence of chenodeoxycholic acid and ursodeoxycholic acid on the hepatic structure of the rat (author's transl)]

Chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) dissolve cholesterol gallstones in man. Since CDCA has caused liver damage in animal experiments we have tried to elucidate the question whether such alterations could occur due to UDCA therapy as well. CDCA and UDCA were fed orally in doses of 20, 90, 150, 250 and 1000 mg/kg body-weight daily to female Wistar-Rats (CDCA: 75 animals; UDCA: 75 animals). After 5, 30 and 60 days we examined the liver by means of light- and electronmicroscopy. After 30 days all animals treated with 1000 mg/kg CDCA had died, whereas there were no pathological findings in the UDCA treated group. By means of electronmicroscopy we detected in the CDCA-group already with 20 mg/kg/day microstructural alterations of the liver that increased with elevation of the dosage and duration of treatment. With UDCA therapy liver tissue showed minimal changes only with 1000 mg/kg. The difference is explained by the decreased rate of transformation of UDCA to lithocholic acid and the lack of toxicity of UDCA in the hepatocyte.     

Prolonged administration of bile salts for gallstone dissolution and its effect on rectal epithelial cell proliferation

Bile acids and cholesterol metabolites may play a role in large bowel carcinogenesis. Currently, the bile acids chenodeoxycholic (CDCA) and ursodeoxycholic acid (UDCA) are being used for dissolution of cholesterol gallstones in surgical high-risk patients. The effect of prolonged exogenous bile acid intake on rectal epithelial cell proliferation, as a marker for preneoplasia, was evaluated in 19 patients selected for treatment. They were divided into two groups: nine patients received CDCA, 15 mg/kg/day for a mean duration of 11.0 months, while 11 patients received UDCA, 10 mg/kg/day for a mean duration of 9.2 months. Rectal biopsies taken before treatment and at one, three, six, and 12 months of treatment were analyzed and evaluated by three proliferative parameters including labeling index (LI), distribution of labeled cells, and total cells per crypt column. No significant alterations in epithelial cell proliferation were observed among patients treated with UDCA or CDCA with the exception of the number of cells per crypt column which, in the latter instance, deviated only slightly from the predicted values. The lack of major persistent alterations in the proliferative behavior of rectal epithelial cells does not justify any change in the selection of patients for gallstone therapy, but cannot exclude the potentially deleterious long-term effects of bile acid treatment.     

Changes in Bile Acid Composition and Effect on Cytolytic Activity of Fecal Water by Ursodeoxycholic Acid Administration: a Placebo-Controlled Cross-over Intervention Trial in Healthy Volunteers

Background: Ursodeoxycholic acid (UDCA) has been shown to affect membrane-damaging effects of bile acids in vitro and fecal bile acid composition in rats. This study evaluates the effect of UDCA on fecal bile acid composition and on cytolytic activity of fecal water in man to clarify the potential chemopreventive role of UDCA for colorectal cancer. Methods: In this placebo-controlled crossover intervention trial, the effect of 900 mg/day UDCA orally in 15 healthy volunteers was studied. At the end of each 4-week period, 72 h feces were collected. Total and individual bile acids in feces were determined by gas chromatography and soluble bile acids were analyzed by high-performance liquid chromatography. Cytolytic activity of fecal water was measured using an erythrocyte lysis assay. Results: In feces, the percentages of primary bile acids--cholic acid (CA) and chenodeoxycholic acid (CDCA)--and of secondary bile acid--deoxycholic acid (DCA)--decreased after supplementation with UDCA, whereas those of UDCA and LCA increased from 2.7 ± 0.4% to 23.7 ± 2.6%, P < 0.0001 and from 26.2 ± 1.2% to 49.4 ± 1.8%, P < 0.0001 respectively. The concentrations of these two bile acids in fecal water also increased after UDCA administration from 7.8 ± 1.9 μmol/l to 47.0 ± 6.7 μmol/l (UDCA), P < 0.0001 and from 2.5 ± 0.6 μmol/l to 18.3 ± 4.1 μmol/l (LCA), P < 0.002, respectively. Cytolytic activity of fecal water was not affected by UDCA. Conclusion: These results do not support a protective effect of UDCA supplementation against colorectal cancer in man.     

Hepatoprotective bile acid 'ursodeoxycholic acid (UDCA)' Property and difference as bile acids.

Ursodeoxycholic acid (UDCA) is a bile acid, which is present in human bile at a low concentration of only 3% of total bile acids. It is a 7beta-hydroxy epimer of the primary bile acid chenodeoxycholic acid (CDCA). UDCA is isolated from the Chinese drug 'Yutan' a powder preparation derived from the dried bile of adult bears. For centuries, Yutan has been used in the treatment of hepatobiliary disorders. In Japan, it has also been in widespread use as a folk medicine from the mid-Edo period. In Japan, not only basic studies such as isolation, crystallization, definition of the chemical structure and establishment of the synthesis of UDCA have been conducted but clinical studies have been conducted. First reports on the effects of UDCA in patients with liver diseases came from Japan as early as 1961. In the 1970s, the first prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution was reported. In late 1980s, a number of controlled trials on the use of UDCA in primary biliary cirrhosis (PBC) were reported. Since then, a variety of clinical studies have shown the beneficial effect of UDCA in liver disease worldwide. To date, UDCA is utilized for the treatment of PBC for which it is the only drug approved by the U.S. Food and Drug Administration (FDA). In recent years, with the advent of molecular tools, the mechanisms of action of bile acids and UDCA have been investigated, and various bioactivities and pharmacological effects have been revealed. Based on the results of these studies, the bioactive substances in bile acids that are involved in digestive absorption may play important roles in signal transduction pathways. Furthermore, the mechanisms of action of UDCA is evidently involved. We reveal the physicochemical properties of UDCA as bile acid and overview the established pharmacological effects of UDCA from its metabolism. Furthermore, we overview the current investigations into the mechanism of action of UDCA in liver disease.     

Differences in the efficacy of ursodeoxycholic acid and bile acid metabolism between viral liver diseases and primary biliary cirrhosis

AIM AND METHODS: The effects of ursodeoxycholic acid (UDCA, 600 mg/day) on liver function test values, and serum and urinary bile acids levels in hepatitis C virus-related chronic hepatitis (CH, n = 39) and liver cirrhosis (LC, n = 25), and in primary biliary cirrhosis (PBC, n = 25) were compared. RESULTS: The percentages of improvement in alanine transaminase (ALT) and gamma-glutamyl transpeptidase (gamma-GTP) in CH were almost the same in LC. The rates of improvement in ALT in PBC were negatively correlated with histological stages in the liver. Total serum bile acid levels in LC rose to the same extent as in CH, but the increases in PBC were significantly smaller at stages 3-4 than stages 1-2. The urinary levels of hydroxylated metabolites of UDCA only slightly increased in LC, but they increased significantly at PBC stages 3-4. CONCLUSIONS: The efficacy of UDCA was preserved in LC, but diminished at PBC stages 3-4. The poor enrichment of UDCA in the bile acid pool and extensive biotransformation of UDCA may cause the limited efficacy of UDCA in the cirrhotic stage of PBC.     

Increase of sulfated ursodeoxycholic acid in the serum and urine of patients with chronic liver disease after ursodeoxycholic acid therapy

The present study was undertaken in order to investigate the influence of ursodeoxycholic acid (UDCA) on the composition of sulfate-conjugated bile acids in the serum and urine of patients with chronic active hepatitis and compensated liver cirrhosis. After a 12 week UDCA treatment (600 mg/day), total serum bile acid concentration increased two-fold in patients with compensated liver cirrhosis and increased slightly in patients with chronic active hepatitis. The percentage of sulfated bile acids significantly increased in patients with both compensated liver cirrhosis and chronic active hepatitis. UDCA made up 63% of the total serum bile acids in compensated liver cirrhosis and 61% in chronic active hepatitis after UDCA treatment. Of the serum bile acids after UDCA treatment, 35.2 and 53.9% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. Urinary excretion of total bile acid and UDCA after UDCA treatment in compensated liver cirrhosis were higher than in chronic active hepatitis. UDCA made up 68% of the total urinary bile acids in compensated liver cirrhosis and 64% in chronic active hepatitis after UDCA treatment. Of the urinary bile acids after UDCA treatment, 51.8 and 54.8% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. UDCA treatment for compensated liver cirrhosis was less effective than for chronic active hepatitis. We found that sulfate conjugation is one of the major metabolic pathways for UDCA after UDCA treatment in chronic liver diseases.     

Liquid crystal formation in ursodeoxycholate-rich human gallbladder bile

We studied liquid crystal formation in bile samples obtained from the patients with radiolucent gallstones who had been administered either ursodeoxycholic acid (UDCA) at a dose of 600 mg/day or chenodeoxycholic acid (CDCA) at 400 mg/day for one week preoperatively. The UDCA/total bile acids ratio was found to range from 50 to 60% and the CDCA/total bile acids ratio ranged from 70 to 80%. Cholesterol molar percent was 5 in UDCA-rich bile and 6 in CDCA-rich bile. Phospholipid molar percentage was about the same in both groups. Liquid crystal formation was confirmed only in the UDCA-rich bile samples but not in the CDCA-rich bile samples. This result suggests that cholesterol in the UDCA-rich bile samples is not solubilized by the bile salt and phospholipid mixed micelles but also consumed to form liquid crystals.     

Effect of Ursodeoxycholic Acid Administration after Liver Transplantation on Serum Liver Tests and Biliary Complications: A Randomized Clinical Trial

Background/Aims: Endogenous hydrophobic bile acids are suspected to be one of the pathogenetic factors of biliary complications after orthotopic liver transplantation (OLT). This study was designed to investigate the effects of hydrophilic ursodeoxycholic acid (UDCA) administration early after OLT on serum liver tests and the incidence of biliary complications. Methods: 112 adult patients undergoing OLT from donation after cardiac death (DCD) were randomized to UDCA (13-15 mg/kg/day for 4 weeks; 56 patients) or placebo (56 patients). Serum liver tests and serum bile acids of all patients and biliary bile acids in patients with T-tube drainage were determined during the 4 weeks after OLT. Biliary complications as well as patient and graft survival were analyzed during a mean follow-up of 41.6 months. Results: UDCA treatment decreased ALT, AST and GGT (p < 0.05) during the 4 weeks after OLT and the incidence of biliary sludge and casts within the 1st year (p < 0.05). However, no differences in the incidence of other biliary complications as well as 1-, 3- and 5-year graft and patient survival were observed. Conclusions: UDCA administration early after DCD-OLT improves serum liver tests and decreases the incidence of biliary sludge and casts within the 1st postoperative year but does not affect overall outcome up to 5 years after OLT.     

Optimum bile acid treatment for rapid gall stone dissolution.

To determine the optimum bile acid regimen for rapid gall stone dissolution, 48 gall stone patients were divided into four groups of 12 according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime chenodeoxycholic acid (CDCA, 12 mg/kg/day) and bedtime or mealtime ursodeoxycholic acid (UDCA, 12 mg/kg/day). An additional 10 patients treated with a combination of CDCA plus UDCA (each 6 mg/kg/day) at bedtime were matched with the 10 patients on bedtime CDCA and the 10 on bedtime UDCA. The gall stone dissolution rates at six and 12 months were determined by standardised oral cholecystography and expressed as the percentage reduction in the gall stone volume after treatment. The gall stone dissolution rate at six months was higher for UDCA than CDCA treatment (median 78% v 48%, p less than 0.01), and for bedtime than mealtime administration (69% v 39%, p less than 0.02). Both differences were greater for stones less than 8 mm diameter. The dissolution rate was faster for combination therapy than for CDCA alone at both six (82% v 36%, p less than 0.05) and 12 months (100% v 54%, p less than 0.05), but was not different from UDCA alone. We conclude that bile acid treatment should be confined to patients with small gall stones and that bedtime administration of combined UDCA and CDCA is likely to provide the most effective and safe combination.     

Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis

The pathogenesis of acute cholecystitis (AC) is controversial. Bile acids may be involved in the pathogenesis of AC because the hydrophobic chenodeoxycholic acid (CDCA) reproduced in vitro the muscle dysfunction observed in AC and was prevented by the hydrophilic ursodeoxycholic acid (UDCA). The present study examined the in vivo effects of UDCA or CDCA on gallbladder muscle dysfunction caused by AC. Guinea pigs were treated with placebo, UDCA, or CDCA for 2 weeks before sham operation or induction of AC by bile duct ligation (BDL) for 3 days. Pretreatment with oral UDCA prevented the defective contraction in response to agonists (acetylcholine [ACh], cholecystokinin 8 [CCK-8], and KCl) that occurs after BDL. Prostaglandin (PG) E(2)-induced contraction remained normal in the placebo and UDCA-treated groups but was impaired in the CDCA-treated group. Treatment with UDCA also prevented the expected increase in the levels of H(2)O(2), lipid peroxidation, and PGE(2) content in the placebo-treated AC group, whereas CDCA caused further increases in these oxidative stress markers. The binding capacity of PGE(2) to its receptors and the activity of catalase were reduced after treatment with CDCA. Treatment with UDCA enriched gallbladder bile acids with its conjugates and reduced the percentage of CDCA conjugates. In contrast, treatment with CDCA significantly decreased the percentage of UDCA in bile. In conclusion, oral treatment with UDCA prevents gallbladder muscle damage caused by BDL, whereas oral treatment with CDCA worsens the defective muscle contractility and the oxidative stress.     

Lack of response to chenodeoxycholic acid in obese and non-obese patients. Role of cholesterol synthesis and possible response to ursodeoxycholic acid.

This paper describes seven patients with radiolucent gallstones in functioning gallbladders who did not respond to chenodeoxycholic acid (CDCA). Despite large doses (greater than or equal to 19 mg CDCA/kg/day), CDCA-rich bile (CDCA conjugates 70-97% of total biliary bile acids) and greater than or equal to one year's treatment, their fasting duodenal bile remained supersaturated with cholesterol and their gallstones did not dissolve. Five patients came to cholecystectomy, gallstone analysis and liver biopsy for measurement of hepatic cholesterogenesis (HMGCoAR activity). In three who stopped CDCA before surgery, the mean HMGCoAR (pmol/mg microsomal protein/min) of 50.2 was higher than in our untreated gallstone controls (32.2 +/- SEM 2.0; P less than 0.05). Two patients who took CDCA until surgery had a mean HMGCoAR of 33.5--more than twice that in CDCA-treated gallstone controls. These findings suggest that non-response to CDCA may be related to high or unsuppressed hepatic cholesterogenesis. In one patient who did not respond to CDCA, treatment with 19 mg ursodeoxycholic acid/kg/day did desaturate his bile.