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PubMed2001

Anti-inflammatory effects of 5-aminosalicylic acid conjugates with chenodeoxycholic acid and ursodeoxycholic acid on carrageenan-induced colitis in guinea-pigs.

Two epimeric bile acid conjugates, 5-aminosalicylic acid-chenodeoxycholic acid (5-ASA-CDCA) and 5-aminosalicylic acid-ursodeoxycholic acid (5-ASA-UDCA), were synthesized to deliver 5-ASA to the large intestine by oral administration. The movement of the conjugates down the gastrointestinal tract and the anti-inflammatory effects on ulcerative colitis were investigated by administering the conjugates to guinea-pigs with an inflammatory bowel disease induced by 2% degraded carrageenan solution. The conjugates were protected from deconjugation in stomach and small intestine and reached the caecum and the colon, where 5-ASA was more easily liberated from 5-ASA-CDCA than from 5-ASA-UDCA. The conjugates at doses equivalent to 50 or 150 mg kg(-1) 5-ASA were orally administered once a day for 4 weeks from the 15th day after starting carrageenan treatment. The body weights and the bleeding scores of occult blood in faeces were measured during the experiment. The number of ulcers in the caecum and the colon were counted after killing the guinea-pigs at the end of the experiment. Rapid onset of efficacy was shown by a significant reduction in bleeding scores within a week after administration of the conjugates. Treatment with the lower dose of 5-ASA-CDCA showed a recovery of body weight and a significantly decreased number of ulcers in the caecum, and the ulcers in the colon had completely disappeared bythe end of the experiment. There was a good correlation found between the number of ulcers in the caecum and the bleeding scores of occult blood in faeces. The findings indicate that both conjugates were sufficiently delivered to the large intestine without deconjugation and that the lower dose of 5-ASA-CDCA is enough for treatment of ulcerative colitis in colonic inflammatory bowel diseases.

Animals↗
PubMed1998

Method for the separation of the unconjugates and conjugates of chenodeoxycholic acid and deoxycholic acid by two-dimensional reversed-phase thin layer chromatography with methyl beta-cyclodextrin.

A simple and efficient method for the separation of individual unconjugated bile acids and their glycine- and taurine-amidated, 3-sulfated, 3-glucosylated and 3-glucuronidated conjugates is described. The method involves the use of a two-dimensional (2D) reversed-phase (RP) high-performance thin-layer chromatographic (HPTLC) technique with methyl beta-cyclodextrin (Me-beta-CD). Five major unconjugated bile acids, chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), ursodeoxycholic acid and lithocholic acid, and their conjugates were examined as the solutes. A high degree of separation of individual bile acids in each homologous series was achieved on a RP-HPTLC plate by developing with aqueous methanol in the first dimension and the same solvent system containing Me-beta-CD in the second dimension. In particular, all of the six 'difficult-to-separate' pairs, unconjugated CDCA and DCA and their conjugated forms with glycine, taurine, sulfuric acid, D-glucose and D-glucuronic acid, were effectively resolved by adding Me-beta-CD in the aqueous mobile phases with the formers having larger mobilities than the latter. The application of this 2D inclusion RP-HPLC method to the separation of glycine-conjugated bile acids in human bile is also described. The present method would be useful for separating and characterizing these bile acids present in biological materials.

Bile↗
PubMed1994

Comparative effects of lovastatin and chenodeoxycholic acid on plasma cholestanol levels and abnormal bile acid metabolism in cerebrotendinous xanthomatosis.

We investigated the effect of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin and the primary bile acid chenodeoxycholic acid (CDCA) on plasma sterol and bile alcohol concentrations and the excretion of bile alcohols in urine in a 38-year-old homozygote with cerebrotendinous xanthomatosis (CTX). Untreated, plasma cholesterol concentrations were less than normal (171 +/- 5 v 185 +/- 3 mg/dL, P < .05) while plasma cholestanol levels were more than 20 times higher than the control mean (2.26 +/- 0.17 v 0.1 +/- 0.1 mg/dL, P < .0001). Plasma and urinary bile alcohol concentrations were markedly increased (12.6 +/- 0.6 and 154 micrograms/mL, respectively, v trace amounts in controls), with the ratio of 5 beta-cholestane-3 alpha,7 alpha,12 alpha, 25-tetrol to 5 beta-cholestane, 3 alpha,7 alpha,12 alpha,23 (22 and 24),25-pentols being 1.6 in plasma and reversed to 0.15 in urine. Treatment with lovastatin (40 mg/d) reduced plasma cholesterol concentrations 13%, but failed to decrease plasma cholestanol or bile alcohol levels. Abundant amounts of bile alcohols continued to be excreted in urine. In contrast, CDCA (750 mg/d) inhibited abnormal bile acid synthesis, as evidence by a 17-fold decrease in total bile alcohol levels in plasma and a 29-fold decrease in urine and the virtual elimination of cholic acid and deoxycholic acid from the bile. Plasma cholestanol concentrations also decreased 85%, but cholesterol levels increased 14%. The combination of CDCA with lovastatin did not improve plasma cholestanol or bile alcohol concentrations compared with CDCA treatment alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Effect of chenodeoxycholic acid on 11beta-hydroxysteroid dehydrogenase in various target tissues.

Glucocorticoids are metabolized by isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). There is some controversy concerning the bile acid, chenodeoxycholic acid (CDCA), as a potential endogenously produced inhibitor of 11beta-HSD. The present experiments were designed to determine the relative specificity of CDCA for both isoforms of 11beta-HSD and to assess the biological relevance of inhibition in vascular tissue. IC(50) values (concentrations which inhibit 50% of the enzyme reaction) were calculated using rat liver microsomes as a source of 11beta-HSD1 dehydrogenase, Leydig cells for 11beta-HSD1 dehydrogenase and reductase, aorta for 11beta-HSD1 dehydrogenase and reductase, and sheep kidney for 11beta-HSD2 dehydrogenase. In each case, CDCA functioned as a potent inhibitor of 11beta-HSD1 dehydrogenase with IC(50) values of ranging from 0.2 to 7 micromol/L in contrast to 37 to 200 micromol/L for 11beta-HSD1 reductase. CDCA exhibited relatively weak inhibitory activity against 11beta-HSD2 from sheep kidney with an IC(50) of 70 micromol/L. The effect of CDCA on vascular contraction was studied in aortic rings isolated from Spague-Dawley rats incubated in medium containing corticosterone 10 nmol/L +/- CDCA (1 micromol/L) for 24 hours. Rings were stimulated with graded concentrations of phenylephrine (PE) (10 nmol/L, 100 nmol/L, and 1 micromol/L). Rings exposed to corticosterone and CDCA consistently demonstrated a greater contractile response at lower doses of PE (63% at PE 10 nmol/L, P <.001; 20% at PE 100 nmol/L, P <.025; and 10% at PE 1 micromol/L, not significant [NS]) compared to control preparations incubated with cortiosterone alone. These studies demonstrate (1) that CDCA preferentially affects 11beta-HSD1 dehydrogenase; (2) CDCA does inhibit 11beta-HSD2 dehydrogenase and 11beta-HSD1 reductase but only at high(er) concentrations exceeding 70 micromol/L and 37 micromol/L, respectively; and (3) inhibition of 11beta-HSD1 dehydrogenase in aortic rings by CDCA (1 micromol/L) enhances the contractile response of corticosterone plus PE.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1979

Conversion of 7-ketolithocholic acid to ursodeoxycholic acid by human intestinal anaerobic microorganisms: interchangeability of chenodeoxycholic acid and ursodeoxycholic acid.

Chenodeoxycholic acid, ursodeoxycholic acid and 7-ketolithocholic acid were incubated with human intestinal bacteria (source: 4 healthy males) at 37 degrees C for 72 hours in an anerobic condition. The bile acids of the products in culture medium were identified by three independent methods, thin layer chromatography, gas-liquid chromatography and GLC-mass spectrometry. Lithocholic acid, ursodeoxycholic acid and 7-ketolithocholic acid were observed in the culture of chenodeoxycholic acid. Lithocholic acid, chenodeoxycholic acid and 7-ketolithocholic acid were observed in the culture of ursodeoxycholic acid. Chenodeoxycholic acid and ursodeoxycholic acid were produced from 7-ketolithocholic acid. These data may suggest that chenodeoxycholic acid and ursodeoxycholic acid are interconvertible via 7-ketolithocholic acid by the mixed culture of human intestinal microorganisms under an anaerobic condition.

Anaerobiosis↗
PubMed2001

Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial. The British-Italian Gallstone Study group.

BACKGROUND: Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization. AIM: To compare the clinical efficacy of combination therapy with ursodeoxycholic acid monotherapy. PATIENTS AND METHODS: A total of 154 symptomatic patients with radiolucent stones (< or = 15 mm) in functioning gallbladders were enrolled from six centres in England and Italy. They were randomized to either a combination of chenodeoxycholic acid plus ursodeoxycholic acid (5 mg.day/kg each) or to ursodeoxycholic acid alone (10 mg.day/kg). Dissolution was assessed by 6-monthly oral cholecystography and ultrasonography for up to 24 months. RESULTS: Both regimens reduced the frequency of biliary pain and there was no significant difference between them in terms of side-effects or dropout rate. Complete gallstone dissolution on an intention-to-treat basis was similar at all time intervals. At 24 months this was 28% with ursodeoxycholic acid alone and 30% with combination therapy. The mean dissolution rates at 6 and 12 months were 47% and 59% with ursodeoxycholic acid, and 44% and 59% with combination therapy, respectively. CONCLUSION: There is no substantial difference in the efficacy of combined ursodeoxycholic acid and chenodeoxycholic acid and that of ursodeoxycholic acid alone in terms of gallstone dissolution rate, complete gallstone dissolution, or relief of biliary pain.

Adult↗
PubMed1988

Propranolol reduces the response of serum bile acids to oral chenodeoxycholic acid, possibly as a reflex reaction to reduced portal blood flow in healthy and cirrhotic subjects.

To evaluate if a drug that affects splanchnic and portal flow reduces intestinal bile acid absorption, we studied the effect of propranolol (40 mg oral dose) both on the response of total bile acids (SBA) to oral chenodeoxycholic acid (CDCA 250 mg) and on the estimated hepatic flow by indocyanine green kinetics in 10 healthy and 14 cirrhotic subjects. In 18 subjects who showed a reduction in resting heart rate of almost -5%, propranolol significantly reduced the SBA area under the curve after CDCA in both healthy (mumol/l/h m +/- SD from 181.7 x 144.9 to 56.5 +/- 36.4 p less than 0.02) and cirrhotic (from 1412.1 +/- 1044.8 to 1129.2 +/- 978.8 p less than 0.01) subjects. Variable but not significant modifications were observed in estimated hepatic flow. These results suggest that the propranolol-induced changes in SBA response to CDCA could be a reflex reaction to changes in splanchnic/portal flow.

Bile Acids and Salts↗
PubMed1974

Increased formation of ursodeoxycholic acid in patients treated with chenodeoxycholic acid.

The formation of ursodeoxycholic acid, the 7 beta-hydroxy epimer of chenodeoxycholic acid, was investigated in three subjects with cerebrotendinous xanthomatosis and in four subjects with gallstones. Total biliary bile acid composition was analyzed by gas-liquid chromatography before and after 4 months of treatment with 0.75 g/day of chenodeoxycholic acid. Individual bile acids were identified by mass spectrometry. Before treatment, bile from cerebrotendinous xanthomatosis (CTX) subjects contained cholic acid, 85%; chenodeoxycholic acid, 7%; deoxycholic acid, 3%; allocholic acid, 3%; and unidentified steroids, 2%; while bile from gallstone subjects contained cholic acid, 45%; chenodeoxycholic acid, 43%; deoxycholic acid, 11%, and lithocholic acid, 1%. In all subjects, 4 months of chenodeoxycholic acid therapy increased the proportion of this bile acid to approximately 80% and decreased cholic acid to 3% of the total biliary bile acids, the remaining 17% of bile acids were identified as ursodeoxycholic acid. After the intravenous injection of [3H]chenodeoxycholic acid, the specific activity of biliary ursodeoxycholic acid exceeded the specific activity of chenodeoxycholic acid, and the resulting specific activity decay curves suggested precursor-product relationships. When [3H]7-ketolithocholic acid was administrated to another patient treated with chenodeoxycholic acid, radioactivity was detected in both the ursodeoxycholic acid and chenodeoxycholic acid fractions. These results indicate that substantial amounts of ursodeoxycholic acid are formed in patients treated with chenodeoxycholic acid. The ursodeoxycholic acid was synthesized from chenodeoxycholic acid presumably via 7-ketolithocholic acid.

Bile Acids and Salts↗
PubMed1989

Tryglycylvasopressin-reduced portal and systemic concentrations of serum bile acids after exogenous chenodeoxycholic acid load in rats as a reflection of reduced splanchnic blood flow.

The effect of triglycylvasopressin (TGVP) on the absorption of chenodeoxycholic acid (CDCA) was investigated in three groups of six rats (controls, CDCA, CDCA + TGVP) through the evaluation of portal and caval serum bile acids (SBA) concentrations after an oral load with CDCA to investigate whether changes in this parameter reflect variations in splanchnic blood flow induced by a vasoconstrictor. The results indicate that CDCA was absorbed and led to a significant increase in SBA. This increase was reduced by TGVP administration: portal blood 380.0 +/- 61.2 vs 279.7 +/- 45.3; caval blood 151.8 +/- 45.7 vs 41.7 +/- 12.5 (mumol/l; mean +/- s.d.). This suggests that variations in SBA concentrations could reflect changes in splanchnic circulation.

Animals↗
PubMed1980

Comparison of the effects between ursodeoxycholic and chenodeoxycholic acids on liver function and structure and bile acid composition in the Rhesus Monkey.

The hepatotoxic potential of the cholelitholytic bile acids, chenodeoxycholic (chenic), and ursodeoxycholic acids, was compared in the rhesus monkey. A placebo-controlled treatment trial with 40 and 120 mg/kg/day doses of chenic acid and ursodeoxycholic acid, respectively, was conducted in 20 animals. Both chenic and ursodeoxycholic acids induced comparable abnormalities of liver function and structure. Liver biopsies, performed before and after 6 mo of treatment, showed the development of distinct light microscopic changes, including inflammation, fibrosis, and ductular proliferation in the portal fields as well as lobular rearrangement with formation of septa and regenerative nodules. Electron microscopy confirmed light microscopy, but showed no specific changes of cell organelles. Light microscopic examination of the kidneys, lungs, heart, intestine, and brain in 10 monkeys, which were sacrificed after 6 mo of controlled bile acid treatment, showed no abnormalities. Biliary lithocholic acid, all of which was unsulfated, increased several-fold to comparable levels in the bile acid-treated groups. Follow-up studies 6 mo after termination of bile acid treatment showed normalization of liver function tests and of bile acid composition as well as a considerable improvement of the histologic abnormalities. However, the restitution of normal liver structure was incomplete, with fibrosis and mild inflammation persisting in the portal fields. Our studies show that, in this primate species, chenic and ursodeoxycholic acids have comparable hepatotoxic effects, which are associated with similar increases of unsulfated lithocholic acid in bile.

Animals↗
PubMed1975

Chenodeoxycholic acid therapy for gallstones: effectiveness, toxicity and influence on bile acid metabolism.

Chenodeoxycholic acid (1 g daily) was administered to 10 patients with gallstones and three patients with biliary stricture and recurrent cholangitis. Four gallstone patients showed diminution or disappearance of stones including one patient whose stone was in the common bile duct. The patients with recurrent cholangitis showed marked improvement in symptoms during treatment. Serum bile acid levels were significantly elevated in 8 gallstone patients during treatment. Liver biopsy in eight gallstone patients during treatment revealed minor changes in five. Lithocholic acid and bile acid sulphates were found in only small amounts in the bile of patients during treatment. No significant trend in biliary lipid composition during treatment was observed. There was no overall trend in the group of patients whose stones disappeared or diminished. Changes in biliary bile acid composition and in bile acid pool sizes were variable following treatment and could not be correlated with the clinical results of treatment. A further trial of chenodeoxycholic acid is recommended in patients with stones in the biliary tree and recurrent cholangitis who are not amenable to surgical treatment.

Adult↗
PubMed2000

Competition in liver transport between chenodeoxycholic acid and ursodeoxycholic acid as a mechanism for ursodeoxycholic acid and its amidates' protection of liver damage induced by chenodeoxycholic acid.

BACKGROUND: Ursodeoxycholic acid has been widely used as a therapeutic agent in cholesterol gallstones and liver disease patients, but its mechanism of action is still under investigation. AIMS: The protective effect of ursodeoxycholic acid, both free, taurine and glycine conjugated, against hepatotoxic bile acids such as chenodeoxycholic acid and its taurine amidate was studied in bile fistula rats and compared with the cholic and taurocholic acid effect. METHODS: Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid, taurocholic acid and cholic acid were infused iv over 1 hour (8 micromol/min/kg) together with an equimolar dose of either taurochenodeoxycholic acid or chenodeoxycholc acid. Bile flow, total and individual bile acid and biliary lactate dehydrogenase and alkaline phosphatase enzymes were measured. RESULTS: Taurochenodeoxycholic acid and chenodeoxycholc acid caused cholestasis and liver damage associated with a decreased bile flow, total and individual bile acids secretion accompanied by a biliary leakage of lactate dehydrogenase and alkaline phosphatase enzymes. Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid and taurocholic acid, on the contrary, were choleretic, inducing an opposite effect on biliary parameters. Simultaneous infusion of taurochenodeoxycholic acid and the protective bile acid resulted in a functional and morphological improvement of the above parameters in the following order: glycine ursodeoxycholic acid > tauroursodeoxycholic acid > ursodeoxycholic acid followed by taurocholic acid; cholic acid was ineffective. CONCLUSIONS: The results show the protective effect of glycine ursodeoxycholic acid, ursodeoxycholic acid and tauroursodeoxycholic acid. This may be due to a facilitated transport of the toxic bile acid into bile; conjugation with taurine is less effective than glycine. Finally, the better protective effect of ursodeoxycholic acid and its amidates with respect to cholic acid and its taurine conjugated form seems to be related to their different lipophilicity and micellar forming capacity.

Alkaline Phosphatase↗