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At least 73 records · Page 4Linked to original sources
PubMed2003

Apoptosis and modulation of cell cycle control by synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid in human prostate cancer cells.

The effects of synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of human prostate carcinoma PC-3 cells were investigated. Whereas CDCA and UDCA had no effects on the growth of cells in a concentration range we have tested, HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed a weak inhibitory activity. This proliferation-inhibitory effect of the synthetic bile acid derivatives was due to the induction of apoptosis, which was confirmed by observing DNA fragmentation, chromatin condensation and cleavage of PARP. Flow cytometric analysis also revealed that the synthetic bile acid derivatives arrested the cell cycle progression at the G1 phase, which effects were associated with inhibition of phosphorylation of pRB and enhanced binding of pRB and E2F-1. They also suppressed Cdk2 and cyclin E-dependent kinase activities without changes of their expressions. Furthermore, the synthetic bile acids increased the levels of Cdk inhibitor, p21WAF1/CIP1, expression and activated the reporter construct of p21WAF1/CIP1 promoter in p53-independent manner, and p21WAF1/CIP1 proteins induced by the synthetic bile acid derivatives were associated with Cdk2 and proliferating cell nuclear antigen. These distinctive features suggest that it is possible to create the new drugs useful for cancer therapy from the synthetic bile acid derivatives as lead compounds.

Apoptosis↗
PubMed1980

Effects of feeding cholic acid and chenodeoxycholic acid on cholesterol absorption and hepatic secretion of biliary lipids in man.

Chenodeoxycholic acid (CDCA), in contrast to cholic acid (CA), reduces cholesterol saturation of bile. The mechanisms for these differences were the object of this study. Investigations were carried out in nine white men; three nonobese subjects and one obese subject were fed a weight-maintenance diet, and five obese patients had a reduced caloric intake for weight reduction. They were given a daily dose of 750-1000 mg CDCA or CA for one month after which they received the other bile acid for another month. The effects of both bile acids on bile acid pool size and hepatic secretion rates of biliary lipids were determined. Total bile acid pools were increased markedly by both CDCA and CA, but to about the same degree for each. Thus, the superior action of CDCA for lowering saturation of bile could not be explained by its effect on the pool sizes of bile acids. On the other hand, hepatic secretion of cholesterol, both during feeding and fasting, was found to be reduced to a greater extent by CDCA than by CA. A theoretical mechanism by which CDCA might lower hepatic outputs of cholesterol is the inhibition of cholesterol absorption. To examine this possibility, cholesterol absorption was estimated by use of an intestinal perfusion technique. No differences were obtained between the two treatment periods for either percentage or net absorption of cholesterol; thus it is unlikely that decreased absorption could account for the reduced cholesterol secretion. Another possibility is that CDCA might affect the interrelations of the three biliary lipids differently than CA. This was explored by measurements of hepatic secretion rates of these lipids. We observed a linear relationship between the secretion rates of bile acids and cholesterol, cholesterol and phospholipids, and bile acids during both treatment periods. However, cholesterol:phospholipid ratios were higher during CA therapy than with CDCA, and they increased still more during fasting in most CA-treated subjects, but not with CDCA. This indicated that there is a marked difference between the two bile acids in the degree of coupling of cholesterol and phospholipids in fasting. We suggest that the reduction in bile sa;uration on CDCA is most likely the result of changes in the interrelations of the different biliary lipids at the site of their secretion and/or inhibition of cholesterol output from the liver because of suppressed cholesterol synthesis in this organ.

Bile↗
PubMed2001

Effects of treatment with deoxycholic acid and chenodeoxycholic acid on the hepatic synthesis of cholesterol and bile acids in healthy subjects.

The degradation of cholesterol to bile acids is regulated by a negative-feedback mechanism by the bile acids, especially the hydrophobic bile acids, returning to the liver via the portal vein. Chenodeoxycholic acid (CDCA) is a potent suppressor of the cholesterol 7alpha-hydroxylase, the rate-determining enzyme in bile acid formation. CDCA may also suppress hepatic 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Conflicting reports have appeared regarding the suppression on bile acid synthesis by the most hydrophobic bile acid of human bile, deoxycholic acid (DCA). To study the suppressive effects of CDCA and DCA on hepatic cholesterol and bile acid synthesis in humans, 10 healthy subjects were treated with CDCA or DCA for 3 weeks in a randomized cross-over study with a washout period of 4 weeks in between. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, reflecting cholesterol 7alpha-hydroxylase activity, and 7-dehydrocholesterol, reflecting HMG CoA reductase activity, and bile acids were repeatedly measured during the study periods. After 3 weeks of treatment with CDCA or DCA, CDCA constituted 70% and DCA 74% of the total serum bile acids, respectively. CDCA and DCA decreased the serum levels of 7alpha-hydroxy-4-cholesten-3-one by 80% and 75%, respectively. Negative correlations between the percentages of CDCA and DCA and the serum concentration of 7alpha-hydroxy-4-cholesten-3-one were obtained. CDCA reduced the serum level of 7-dehydrocholesterol by 29%, whereas treatment with DCA tended to increase the level of 7-dehydrocholesterol. Treatment of healthy subjects with CDCA and DCA reduces bile acid synthesis. CDCA also inhibits cholesterol synthesis, whereas DCA does not.

Adult↗
PubMed1983

Chenodeoxycholic acid administration monitored by serum bile acid profiles: a dose-response study.

Serum bile acid analysis was used to monitor the bile acid composition of bile in 16 healthy male volunteers before and during the oral administration of different doses of the gallstone-dissolving bile acid, chenodeoxycholic acid. Daily chenodeoxycholic acid ingestion increased the percentage of this bile acid in bile to a new steady-state level after two to three weeks. Doses of 125, 250, 500, and 750 mg/day significantly increased the proportion of chenodeoxycholic acid in bile from 41% to 55, 61, 78, and 79%, respectively, during the fourth week of ingestion. The results indicate that useful information concerning chenodeoxycholic acid-induced changes in the bile acid composition of bile can be obtained solely by serum bile acid analysis, and bile collection by duodenal intubation can be avoided.

Adult↗
PubMedDate not supplied

Ursodeoxycholic acid vs. chenodeoxycholic acid as cholesterol gallstone-dissolving agents: a comparative randomized study.

Cholesterol gallstones are dissolved in man by chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA). To test the comparative efficacy of these two cholelitholytic bile acids, 223 gallstones patients were randomly treated with either UDCA or CDCA at two different doses: 7 to 8 mg per kg per day and 14 to 15 mg per kg per day. Efficacy and factors influencing dissolution (dose, size of the stones, and time) were evaluated after 3, 6, and 12 months of treatment. UDCA was significantly more efficacious than was CDCA after 3 and 6 months of treatment, whereas after 12 months, no significant differences were observed. UDCA was equally effective at high and low doses, both on small and large stones. CDCA was significantly more effective at high doses and on small stones. Seventy-four per cent of the total dissolutions with UDCA and 42% with CDCA occurred within the first 6 months of treatment. Diarrhea and hypertransaminasemia occurred only in the CDCA-treated patients. We conclude that UDCA seems to be the bile acid of choice in dissolving cholesterol gallstones.

Adolescent↗
PubMed1997

Effect of side chain length on biotransformation, hepatic transport, and choleretic properties of chenodeoxycholyl homologues in the rodent: studies with dinorchenodeoxycholic acid, norchenodeoxycholic acid, and chenodeoxycholic acid.

To assess the effect of side chain length on the metabolism and physiological effects of homologues of chenodeoxycholic acid (CDCA), dinorCDCA, the C22 homologue, was synthesized and its hepatic biotransformation, transport kinetics, and choleretic properties were defined in rat and hamster biliary fistula and in isolated perfused rat liver. Results were compared with those of norCDCA, the C23 homologue, and of CDCA, the natural C24 homologue. In the rat, dinorCDCA was secreted mostly in unconjugated form (the majority as dinor-alpha-muricholic acid); the remainder was glucuronidated. In the hamster, glucuronidation was greater, and the unconjugated fraction contained equal parts of dinorCDCA and 5beta-hydroxy-dinorCDCA. NorCDCA was glucuronidated extensively (70%, rat; 40%, hamster). CDCA, in contrast, was efficiently amidated with taurine or glycine. In the perfused liver, the initial uptake rate of all three homologues was identical; later, regurgitation and/or cholehepatic shunting of dinorCDCA and norCDCA, but not of CDCA, occurred. In rats and hamsters with biliary fistulas, dinorCDCA and norCDCA, but not CDCA, induced a bicarbonate-rich hypercholeresis of canalicular origin. Hypercholeresis was not induced by the taurine conjugate of dinorCDCA. Hepatobiliary retention of both dinorCDCA and norCDCA occurred, consistent with efficient ductular absorption (calculated to be 94%) and cholehepatic cycling of the unmetabolized bile acids. It is concluded that dinorCDCA, as norCDCA, is inefficiently amidated, is metabolized as a xenobiotic, and induces hypercholeresis. DinorCDCA is the first dihydroxy bile acid to be identified that is secreted largely in unconjugated form in bile.

Animals↗
PubMed1995

Effects of ursodeoxycholic acid and chenodeoxycholic acid on human hepatocytes in primary culture.

Hepatic bile acid concentrations are elevated in chronic cholestasis because of reduced canalicular excretion and active ileal absorption of the fraction eliminated in the gut. Ursodeoxycholic acid (UDCA) reduces the intestinal absorption of endogenous bile acids, thereby diminishing the concentrations to which liver cells are exposed. In the isolated perfused liver (in which vectorial bile acid transport is maintained), UDCA reduces the cytotoxic and cholestatic effects of endogenous bile acids. As a result, it has been suggested that UDCA or one of its conjugates could have a direct protective effect on hepatocyte structure and function. We therefore studied the effects of chenodeoxycholic acid (CDCA) and tauroursodeoxycholic acid (TUDCA) alone and in combination on the viability and certain functions of human hepatocytes in primary culture. TUDCA did not affect intracellular concentrations of CDCA when added concomitantly. In other experiments, CDCA (100 to 500 mumol/L) induced concentration-dependent increases in lactate dehydrogenase (LDH) leakage and decreases in cellular protein synthesis and albumin secretion. Neither TUDCA nor UDCA had similar effects at the same concentrations, nor did they have a protective effect when added concomitantly with CDCA at equimolar or twice-equimolar concentrations. These results suggest that UDCA has no direct cytoprotective effect when the bile acid concentrations to which human hepatocytes are exposed are unchanged. They also suggest that the hepatoprotective effect of UDCA in cholestatic human liver diseases and in the isolated perfused liver loaded with hydrophobic bile acids occurs through its effect on intestinal and hepatocyte transport systems.

Bile Acids and Salts↗
PubMed2002

Effect of chenodeoxycholic acid on the toxicity of 5alpha-cyprinol sulfate in rats.

Attempts are made to elucidate the effect of bile acid chenodeoxycholic acid on the toxicity of bile alcohol 5alpha-cyprinol in rats. Twenty-four male Wistar rats were divided into four groups and treated orally at 3-days periodic treatment with each 160 mg/kg of 5alpha-cyprinol sulfate/chenodeoxycholic acid (9:1), 5alpha-cyprinol sulfate and chenodeoxycholic acid for 19 days. After treated with 5alpha-cyprinol sulfate/chenodeoxycholic acid (9:1), 5alpha-cyprinol sulfate and chenodeoxycholic acid, the relative ratios of liver and kidney weight to body weight, the concentrations of red blood cells (RBC), hemoglobin and hematocrit in the blood, the levels of aspartate transferase (AST), alanine transferase (ALT), alkaline phosphatase (ALP), blood urea nitrogen (BUN) and creatinine in the plasma, and the levels of BUN and creatinine in the urine of rats were significantly increased, but body weight of rats and the levels of Na(+), K(+), Ca(++) in the urine of rats were significantly decreased, especially for both groups of 5alpha-cyprinol sulfate/chenodeoxycholic acid (9:1) and 5alpha-cyprinol sulfate. The pathological examination of liver and kidney also showed the cell enlargement and lesion in cell integrity in these treated groups, especially for both groups with 5alpha-cyprinol sulfate/chenodeoxycholic acid (9:1) and 5alpha-cyprinol sulfate. The toxicity of 5alpha-cyprinol sulfate/chenodeoxycholic acid (9:1) and 5alpha-cyprinol sulfate was similar to each other, and the toxic effect of chenodeoxycholic acid was less.

Animals↗
PubMed1994

Effects of side chain length on ionization behavior and transbilayer transport of unconjugated dihydroxy bile acids: a comparison of nor-chenodeoxycholic acid and chenodeoxycholic acid.

13C-NMR spectroscopy was used to examine the effect of side chain length on the ionization properties and transmembrane transport rate of 3 alpha,7 alpha-dihydroxy bile acids. When solubilized in taurocholate micelles, [23-13C]nor-chenodeoxycholic acid (nor-CDCA) had a pKa of 6.1, similar to that of CDCA (pKa 6.2), its C24 homologue. In unilamellar phosphatidylcholine vesicles, the pKa of nor-CDCA was 7.0, whereas that of CDCA was 6.6. Lineshape analysis indicated that the rate of ionization of nor-CDCA as a micellar solute or as a vesicle component was very slow (0.4 x 10(5) sec-1) compared to that of acetic acid in water (8.7 x 10(5) sec-1). Lineshape analysis of spectra of the protonated form of nor-CDCA at acidic bulk pH indicated that the transbilayer transport rate of nor-CDCA (580 sec-1) was six times faster than that of CDCA (100 sec-1). It is proposed that the shorter side chain of the nor-CDCA molecule causes it to reside more deeply inside the vesicle bilayer than CDCA, explaining its weaker ionization and more rapid flip-flop rate. These in vitro experiments imply that, in vivo, a given C23 nor-dihydroxy bile acid will ionize less readily when present in membranes, and it will also flip-flop faster than its C24 homologue.

Biological Transport↗
PubMed1989

7-Methyl bile acids: effects of chenodeoxycholic acid, cholic acid, and their 7 beta-methyl analogues on the formation of cholesterol gallstones in the prairie dog.

The purpose of this study was to compare the effects of the naturally occurring bile acids (chenodeoxycholic acid and cholic acid) with their 7-methyl analogues (3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid) on gallstone formation and prevention and cholesterol metabolism in the prairie dog. Sixty animals were fed a semipurified diet, containing 0.4% cholesterol, with one of the following acids (0.1%): chenodeoxycholic, cholic, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic, or 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid. This concentration of dietary bile acids amounts to a dose of 27-30 mg/kg.day. After 8 wk, 89% of control animals had gallstones and 94% had cholesterol crystals. Chenodeoxycholic and 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acids decreased the incidence of gallstones to 50%. Cholic acid and 3 alpha,7 alpha,12 alpha-tri-hydroxy-7 beta-methyl-5 beta-cholanoic acid did not prevent gallstone formation. The liver cholesterol level was decreased by chenodeoxycholic acid, whereas cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids increased serum and liver cholesterol. Each administered bile acid became the predominant biliary bile acid and 7-methyl analogues did not increase secondary bile acids. Fecal analysis of radioactive metabolites using 14C-labeled 7-methyl analogues showed that these compounds are resistant to bacterial 7-dehydroxylation. It was concluded that 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid inhibited gallstone formation as effectively as chenodeoxycholic acid, whereas both cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids were not effective. The effects of 7-methyl analogues on the parameters of cholesterol metabolism that we studied were similar to those of their parent compounds, chenodeoxycholic and cholic acids. Thus, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid but not 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid offers promise in cholelitholytic therapy for the prevention and possibly dissolution of cholesterol gallstones.

Animals↗
PubMed1986

Effect of ursodeoxycholic acid and chenodeoxycholic acid on cholesterol and bile acid metabolism.

Orally administered UDCA dramatically reduces the secretion of cholesterol into the bile. During UDCA therapy cholesterol balance is maintained by a reduction in both the relative and absolute absorption of cholesterol and, perhaps, by a combined moderate enhancement of bile acid synthesis and a suppression of cholesterol production. The percentage of UDCA in the bile is limited by the inability of UDCA to suppress bile acid synthesis from cholesterol and by the conversion of UDCA to CDCA by the intestinal bacteria.

Animals↗
PubMed2004

Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces.

Ursodeoxycholic acid-producing bacteria are of clinical and industrial interest due to the multiple beneficial effects of this bile acid on human health. This work reports the first isolation of 7-epimerizing bacteria from feces of a healthy volunteer, on the basis of their capacity to epimerize the primary bile acid, chenodeoxycholic acid, to ursodeoxycholic acid. Five isolates were found to be active starting from unconjugated chenodeoxycholic acid and its tauro-conjugated homologue, but none of these strains could epimerize the glyco-conjugated form. Biochemical testing and 16S ribosomal DNA sequencing converged to show that all five isolates were closely related to Clostridium baratii (99% sequence similarity), suggesting that this bacterial species could be responsible at least partially, for this bioconversion in the human gut.

Aged↗
PubMed1990

Treatment of chronic liver disease caused by 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency with chenodeoxycholic acid.

Deficiency of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase, the second enzyme in the sequence that catalyses the synthesis of bile acids from cholesterol, leads to chronic liver disease in childhood as well as to malabsorption of fat and fat soluble vitamins. A 4 year old boy with this condition has been successfully treated by oral administration of a bile acid--chenodeoxycholic acid. He had been jaundiced since birth, grew poorly because of rickets, and had severe pruritus. Plasma transaminase activities were persistently raised. Chenodeoxycholic acid 125 mg twice daily for two months, and then 125 mg daily, cured his jaundice and pruritus, returned his transaminase activities to normal, and eliminated the need for calcitriol for prevention of rickets. On this treatment he has so far remained well for two years. A diagnosis of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency should be considered in any child with unexplained chronic hepatitis or cirrhosis, especially if the liver disease is accompanied by a clinically obvious malabsorption of fat soluble vitamins. A simple colorimetric test of the urine confirms the diagnosis and effective treatment can be started.

3-Hydroxysteroid Dehydrogenases↗