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PubMed1995

Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters.

BACKGROUND/AIMS: The effectiveness of ursodeoxycholic acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic acid but with similar detergency. METHODS: After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of taurochenodeoxycholic acid was evaluated in bile fistula rats after intraduodenal coinfusion. RESULTS: 6-Fluoro-ursodeoxycholic acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile acids (15% ursodeoxycholic acid). The 6-fluoro analogue prevented the hepatotoxic effects of taurochenodeoxycholic acid. CONCLUSIONS: The results suggest that 6-fluoro-ursodeoxycholic acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.

Albumins↗

PubMed1998

Dietary inulin lowers plasma cholesterol and triacylglycerol and alters biliary bile acid profile in hamsters.

The mechanisms by which inulin may elicit its lipid-lowering effect are not well elucidated. To examine the lipid-lowering potential of inulin and especially its effect on bile acid metabolism, male golden Syrian hamsters were fed semipurified diets containing 20 g/100 g fat, 0.12 g/100 g cholesterol and 0 (control), 8, 12 or 16% inulin for 5 wk. Plasma total cholesterol concentrations were significantly lowered by 18, 15 and 29% in hamsters fed 8, 12 and 16% inulin, respectively. Dietary inulin specifically decreased VLDL cholesterol, which was significantly lower in hamsters fed 16% inulin compared with controls (1.1 +/- 0.3 vs. 2.9 +/- 0.6 mmol/L). LDL and HDL cholesterol were not significantly affected by dietary inulin. Plasma triacylglycerol was significantly reduced by 40 and 63% in hamsters fed 12 and 16% inulin, respectively. Hepatic total cholesterol and particularly esterified cholesterol accumulation were significantly lower in hamsters fed 8% inulin compared with controls. All three levels of dietary inulin caused distinct alterations in the bile acid profile of gallbladder bile. Taurochenodeoxycholic acid was significantly lower, whereas glycocholic and glycodeoxycholic acid were greater in hamsters fed inulin. Daily fecal bile acid excretion (micromol/d) tended to be greater (P = 0.056) in inulin-fed hamsters compared with controls, whereas daily neutral sterol excretion was not affected. These data demonstrate that the lipid-lowering action of inulin is possibly due to several mechanisms, including altered hepatic triacylglycerol synthesis and VLDL secretion and impaired reabsorption of circulating bile acids.

Animals↗

PubMed1986

Sulfated and nonsulfated bile acids in urine of patients with biliary atresia: analysis of bile acids by high-performance liquid chromatography.

To elucidate urinary bile acid patterns in patients with biliary atresia (BA), 15 sulfated and nonsulfated bile acids in urine were separately measured by high-performance liquid chromatography. This relatively simple technique for fluorescence detection utilizes the enzyme 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) to reveal urinary bile acid patterns. By this method, recovery rates of sulfated and nonsulfated bile acids in urine were satisfactory, and this analysis was shown to be applicable to clinical situations. In 10 patients with BA, the mean level of total bile acids in urine (23.35 +/- 18.51 mumol/day) was seven times higher than the mean level in eight normal infants (3.05 +/- 2.05 mumol/day). In the infants with BA, the mean level of total sulfated bile acids was about half of the total bile acid level. The main components of urinary nonsulfated bile acids in BA were glycocholic acid (6.21 +/- 5.55 mumol/day) and taurocholic acid (2.28 +/- 1.33 mumol/day), whereas the main components of the urinary sulfated bile acids were glycochenodeoxycholic acid (4.58 +/- 6.97 mumol/day) and taurochenodeoxycholic acid (3.67 +/- 3.54 mumol/day). Chenodeoxycholic acid, which is relatively toxic to the liver, may more easily be conjugated with sulfate and, hence, excreted into urine at a faster rate than cholic acid. Marked individual variations in urinary bile acid patterns were observed not only in BA patients but also in normal controls.

Adult↗

PubMed1988

Determination of individual serum bile acids in chronic liver diseases: fasting levels and results of oral chenodeoxycholic acid tolerance test.

Fifteen bile acids in serum of 5 normal subjects and 21 patients with chronic liver diseases were fractionated by high performance liquid chromatography. Fasting total bile acids (TBA), glycocholic acid, taurocholic acid, glycochenodeoxycholic acid (GCDCA), and taurochenodeoxycholic acid (TCDCA) were significantly increased in patients with liver cirrhosis as compared with normal subjects. The cholic acid (CA) level and the ratio of the sum of free and conjugated CA to the sum of free and conjugated chenodeoxycholic acid (CDCA) were significantly elevated in patients with compensated as compared with decompensated liver cirrhosis, and were useful for differentiation of the two conditions. Serum bile acid levels were determined after oral administration of 500 mg of CDCA in the 5 normal subjects and 11 patients with liver disease. The TBA level reached a peak 90 min after CDCA administration in patients with chronic hepatitis and after 120 min in those with liver cirrhosis. The increase in the TBA level was significantly greater in patients with liver disease than in normal subjects. CDCA, GCDCA, and TCDCA showed changes similar to those in TBA. In patients with decompensated liver cirrhosis, the reduction in the TBA and CDCA levels after the peaks was slow, and GCDCA and TCDCA levels continued to increase until 180 min after the administration of CDCA. The TBA and CDCA levels 180 min after CDCA administration were significantly different among normal subjects, patients with chronic hepatitis, those with compensated liver cirrhosis, and those with decompensated liver cirrhosis, suggesting the usefulness of CDCA administration in differentiation of these conditions.

Bile Acids and Salts↗

PubMed1998

Effect of different varieties of pectin and guar gum on plasma, hepatic and biliary lipids and cholesterol gallstone formation in hamsters fed on high-cholesterol diets.

The effect of high- (hePE) and low- (lePE) esterification pectin and high- (hvGG) and low-(lvGG) viscosity guar gum on plasma, hepatic and biliary lipids and on prevention of cholesterol gallstones was investigated in male golden Syrian hamsters (Mesocricetus auratus). Hamsters were fed on cholesterol-rich (4 g/kg), gallstone-inducing diets for 6 weeks. The diets were supplemented with 80 g hePE, lePE, hvGG or lvGG/kg or 80 g additional cellulose/kg. No significant differences in plasma total cholesterol and triacylglycerol concentrations between hvGG and lvGG and the gallstone-inducing or cellulose-enriched diets were observed. The hePE diet produced a 16% (non-significant) reduction in total plasma cholesterol but significantly decreased the plasma triacylglycerol level by 45%. The lePE diet caused only minor changes in plasma lipids. Hepatic cholesterol concentrations were significantly higher in hamsters fed on hvGG, lvGG, hePE or lePE primarily due to the accumulation of esterified cholesterol. Supersaturated bile samples, with lithogenic indices ranging from 1.6 to 2.0, were determined with all diets. The hePE and lePE diets slightly altered the bile acid profile by increasing glycocholic acid and decreasing taurochenodeoxycholic acid concentrations resulting in a higher cholic:chenodeoxycholic acid ratio. Cholesterol gallstone formation was not substantially inhibited by the two varieties of pectin and guar gum. The hvGG, lvGG, hePE and lePE diets did not alter faecal weight and caused only minor increases in faecal bile acid excretion. In general, the present findings demonstrate that dietary pectins and guar gums had only minor effects on cholesterol metabolism and did not prevent cholesterol gallstone formation in this hamster model. Possible explanations for this lack of a distinct response to pectin and guar gum are discussed.

Animals↗

PubMed2005

Effect of tamoxifen and raloxifene on cholesterol transformation to bile acids in ovariectomized rats.

Tamoxifen is used as adjuvant therapy for prevention and treatment of metastatic breast cancer, whereas raloxifene is approved for osteoporosis and is being investigated for breast cancer prevention. The most important aspects of these therapies are focused on their influence on bone and lipid metabolism. Several studies have reported the effect of tamoxifen and raloxifene on plasma lipids. Approximately 40% of total cholesterol removal occurs by conversion to bile acids, a process that takes place in the liver. The aim of the present study was to evaluate the influence of tamoxifen and raloxifene on the conversion of cholesterol to bile acids in estrogen-deficient in rats. The study included 40 female Wistar rats, divided into four groups: sham-operated controls, ovariectomized controls, ovariectomized rats treated with tamoxifen and ovariectomized rats treated with raloxifene. After 42 days of drug administration, bile was collected under anesthesia following administration of radioactive [4-(14)C]cholesterol and assayed for total (14)C radioactivity; (14)C-labeled bile acids were determined by the use of isotopic techniques after initial separation by thin-layer chromatography. Ovariectomy caused decreased excretion of bile and bile acids. Administration of tamoxifen and raloxifene significantly reduced the excretion of (14)C-labeled bile and bile acids compared with ovariectomized controls. Tamoxifen therapy significantly reduced the excretion of taurocholic acid and glycochenodeoxycholic plus glycodeoxycholic acids, and excretion of cholic, litocholic and chenodeoxycholic plus deoxycholic acids was increased. Raloxifene significantly reduced the excretion of taurocholic, glycocholic and litocholic acids, taurochenodeoxycholic plus taurodeoxycholic acids, as well as chenodeoxycholic plus deoxycholic acids. The results of the present study suggest that tamoxifen and raloxifene did not reverse the changes in bile composition induced by estrogen deficiency. The decreased concentration of trihydroxy bile acids during therapy with raloxifene might decrease the risk of gallstone formation, although this hypothesis requires further investigation.

Animals↗

PubMed1983

7 alpha-Dehydroxylation of bile acids by resting cells of an unidentified, gram-positive, nonsporeforming anaerobic bacterium.

Transformation of bile acids by washed whole cells of strain HD-17, an unidentified gram-positive anaerobic bacterium isolated from human feces, was studied. 7 alpha-Dehydroxylase was produced only during adaptive growth on medium containing 7 alpha-hydroxy bile acids. Both the extent of hydroxylation and the state of conjugation of the bile acids had marked effects on the induction of the enzyme, and the order of the enzyme induction was conjugated cholic acid much greater than cholic acid greater than taurochenodeoxycholic acid greater than or equal to chenodeoxycholic acid. The addition of excess glucose to the growth medium appreciably reduced the enzyme level. The induced enzyme required strict anaerobic conditions for activity and had an optimal pH range of 6.5 to 7.5. In contrast with the induction of the enzyme, the induced enzyme showed a low degree of substrate specificity between cholic acid and chenodeoxycholic acid, with some preference for the former. In addition, the organism contained 3 alpha-, 7 alpha-, and 12 alpha-hydroxysteroid dehydrogenases, and the addition of bile acids to the medium somewhat enhanced the production of the oxidoreductases. The dehydrogenations were obviously stimulated by oxygen as a terminal electron acceptor. The organism also contained bile salt hydrolase.

Aerobiosis↗

PubMed1971

Effect of intragastric bile salts on ionic movement across normal human gastric mucosa after intravenous atropine.

The effect of intravenous atropine (2.0 mg/70 kg) and intragastric bile salts (5.0-5.5 mM) on ionic fluxes across the gastric mucosa was studied. Serial instillations of bile salts, in 200 ml 160 m-equiv/l HCl with (51)Cr as a non-absorbable indicator, were performed in eight normal subjects. Five subjects received a bile salt mixture of 84% taurocholic acid, 14% taurodeoxycholic acid, and 2% taurochenodeoxycholic acid. With HCl alone (controls) the mean net flux into the lumen was 1.4 m-equiv H(+), 2.9 m-equiv Cl(-), 1.5 m-equiv Na(+), and 0.26 m-equiv K(+) per 15 minutes after the first instillation. Where atropine plus bile salt was given the loss from the lumen was 5.4 m-equiv H(+) (p < 0.01) and 1.9 m-equiv Cl(-) (p < 0.05) and movement into the lumen was 3.2 m-equiv Na(+) (p < 0.01) and 0.20 m-equiv K(+) in the corresponding period. Similar but smaller ion flux changes occurred in three subjects who received atropine and pure taurodeoxycholic acid. The net loss of H(+) from the gastric lumen was greater after atropine-bile salts than that shown in previous studies with bile salts alone. It is postulated that atropine reduced the volume of endogenous HCl secretion unmasking the loss of H(+).

Adult↗

PubMed1987

Potential tumor-promoting activity of bile acids in rat glandular stomach.

The potential tumor-promoting and -initiating activities of bile acids in the glandular stomach mucosa of F344 rats after administration by gastric intubation were studied. Taurocholic acid sodium salt at doses of 300 to 1200 mg/kg body weight and glycocholic acid sodium salt at doses of 400 to 1200 mg/kg body weight induced up to 100-fold increases in ornithine decarboxylase activity with maxima after 4 hr and up to 10-fold increases in replicative DNA synthesis with maxima after 16-17 hr in the pyloric mucosa of the stomach. Taurodeoxycholic acid sodium salt, taurochenodeoxycholic acid sodium salt and glycocholic acid also induced high ornithine decarboxylase activity, and glycodeoxycholic acid sodium salt and glycochenodeoxycholic acid sodium salt caused slight induction of ornithine decarboxylase activity, but taurolithocholic acid sodium salt did not induce ornithine decarboxylase activity at all in the pyloric mucosa of the stomach. Glycocholic acid sodium salt did not induce unscheduled DNA synthesis in the pyloric mucosa of the stomach. The present results suggest that six bile acids, but not taurolithocholic acid sodium salt, have potential tumor-promoting activities in the pyloric mucosa of rat stomach and that glycocholic acid sodium salt has no potential tumor-initiating activity in the pyloric mucosa of rat stomach.

Animals↗

PubMed1978

Bile acid clearance and biocompatibility of XAD-4 haemoperfusion.

The clearance of bile acids from human blood or human albumin solutions obtained by perfusion through 100 g XAD-4 at 100 ml/min was (in ml/min): 21 for taurocholic acid, 3 for taurochenodeoxycholic acid, 18 for glycholic acid and 2 for glychenodeoxycholic acid. Saturation effects were absent up to 7 mumole bile acid bound per gram XAD-4. Haemoperfusion (100 g XAD-4, 100 ml/min) of cholestatic dogs resulted in the removal of up to 400 mumole bile acid in 3 hours. The calculated amount of bile acid stored in tissue depots was large with respect to the amount present in the circulation. A steady state between the mobilization of the tissue pool of bile acids and the removal of bile acids from the blood was established during the perfusion. Measurements of electrolytes enzyme activities and cellular elements showed severe losses of thrombocytes and leucocytes only. Contact with XAD-4 was the cause of the platelet loss where as omission of the resin from the perfusion system did not effect the leucocyte loss. The thrombocyte loss was reduced by the addition of citrate. Differentiation of the leucocytes showed that primarily the segmental granulocytes were sequestrated.

Animals↗

PubMed1993

Bile reflux in columnar-lined Barrett's oesophagus.

Total and individual bile acid concentrations in the oesophageal aspirates from 30 patients with Barrett's oesophagus were compared with those from 15 patients with oesophagitis and 15 normal subjects. The highest total bile acid concentrations were found in the Barrett's patients and this was statistically significant when compared with controls but not oesophagitis patients. However, when the 95th percentile value of bile acid concentration in the normal subjects was taken as the 'cut-off' level, a significantly higher number of Barrett's patients (15/30) were bile refluxers than were the oesophagitis patients (3/15). Glycocholic and taurocholic acids were the predominant bile acids detected, but taurochenodeoxycholic acid was also present in significant amounts in the patients with oesophagitis. It is possible that bile reflux contributes to the development of Barrett's oesophagus.

Aged↗

PubMed1994

Changes in bile acid composition of serum and gallbladder bile in bile duct ligated dogs.

Biliary obstruction was produced by surgical ligation of the common bile duct to observe alterations in serum bile acid composition. The percent composition of serum bile acids was found to change with time. Taurocholic acid increased on day 3 and accounted for more than 90% of the total bile acids in all dogs, however it decreased after day 7. The percentage of taurochenodeoxycholic acid (TCDC) and taurodeoxycholic acid (TDC) decreased to 4.2-6.0% and 0.2-0.7% on day 3, respectively. However, the percentage of TCDC increased after day 7 in all dogs and reached greater than 20% on day 14 in 2 dogs, whereas the percent TDC after bile duct ligation remained low in all dogs. Glycolithocholic acid, which was not identified in normal dog sera, was detected on day 3 and remained throughout the study in all dogs. Bile acid composition of gallbladder bile sampled on day 35 was similar to the serum bile acid composition on the same day. This indicates that the bile acids refluxed into the circulation in these dogs. In the present study, total cholic acid to chenodeoxycholic acid (C:CDC) ratio increased to 15.5-22.3 at three days post bile duct ligation and after the day 14, the C:CDC ratio decreased to its pre-ligation value or below. In contrast, the glycine conjugated to taurine conjugated bile acids (G:T) ratio did not change. Therefore, at this time, the G:T ratio would not be usable as an indicator of liver disease in dogs while it may be possible to use the C:CDC ratio.

Animals↗

PubMed1993

Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes.

The mechanisms by which hydrophobic bile acids are toxic to the liver are unknown. To determine whether the generation of free radicals is involved in the hepatotoxicity of bile acids, freshly isolated rat hepatocytes were incubated with individual bile acids (100 to 200 mumol/L) for 4 hr. Hepatocyte viability (trypan blue exclusion) declined to 40% to 50% in incubations with taurochenodeoxycholic acid and taurolithocholic acid, whereas taurocholic acid and tauroursodeoxycholic acid were not toxic. Lipid peroxidation was significantly associated with the loss of cell viability. Preincubation with different antioxidants-D-alpha-tocopheryl succinate, D-alpha-tocopherol, diphenyl-p-phenylenediamine, superoxide dismutase, catalase, superoxide dismutase + catalase, deferoxamine or apotransferrin-protected against the loss of viability and inhibited lipid peroxidation in cells incubated with 200 mumol/L taurolithocholic acid. alpha-Tocopheryl succinate added after 90 min of incubation with taurolithocholic acid ameliorated further hepatocyte toxicity and lipid peroxidation. Incubation of hepatocytes with 500 mumol/L of taurochenodeoxycholic acid or taurolithocholic acid under a low oxygen tension (9% O2) similarly caused lipid peroxidation and cell injury that was reversed by preincubation with D-alpha-tocopherol. These data suggest that oxygen free radicals may be involved in the pathogenesis of bile acid hepatotoxicity.

Animals↗

PubMed1993

Tauroursodeoxycholate and tauro-beta-muricholate exert cytoprotection by reducing intrahepatocyte taurochenodeoxycholate content.

Cytoprotection by tauroursodeoxycholic acid and tauro-beta-muricholic acid against taurochenodeoxycholic acid-induced toxicity was examined with reference to intracellular bile acid content in primary cultured rat hepatocytes. In comparison with levels in the group administered taurochenodeoxycholic acid 1 mmol/L alone, lactate dehydrogenase levels in the culture medium decreased significantly in groups simultaneously administered taurochenodeoxycholic acid 1 mmol/L and tauroursodeoxycholic acid 0.5 to 2 mmol/L or tauro-beta-muricholic acid. Results of the trypan blue uptake test indicated that the lactate dehydrogenase release was indeed caused by cell damage. After the administration of tauroursodeoxycholic acid 2 mmol/L or tauro-beta-muricholic acid 2 mmol/L, intracellular taurochenodeoxycholic acid content was consistently reduced to half of that after administration of taurochenodeoxycholic acid alone. Simultaneous administration of dibutyl cyclic AMP also reduced intracellular taurochenodeoxycholic acid content and lactate dehydrogenase release. Being rinsed with tauroursodeoxycholic acid and tauro-beta-muricholic acid after being precultured in taurochenodeoxycholic acid 1 mmol/L also markedly reduced their taurochenodeoxycholic acid content. Taurocholic acid caused limited reduction of intracellular taurochenodeoxycholic acid but not suppression of lactate dehydrogenase release. Taurodehydrocholic acid showed no reduction of taurochenodeoxycholic acid content and no decrease of lactate dehydrogenase release. Although only small amounts of tauroursodeoxycholic acid or tauro-beta-muricholic acid were found to accumulate in hepatocytes, taurocholic acid increased as if replacing taurochenodeoxycholic acid. The results suggest that tauroursodeoxycholic acid or tauro-beta-muricholic acid may exert cytoprotective effects by lowering intracellular taurochenodeoxycholic acid levels associated with their optimal hydrophilicity.

Animals↗

PubMed1998

The effect of idebenone, a coenzyme Q analogue, on hydrophobic bile acid toxicity to isolated rat hepatocytes and hepatic mitochondria.

Oxidant stress induced by hydrophobic bile acids has been implicated in the pathogenesis of liver injury in cholestatic liver disorders. We evaluated the effect of idebenone, a coenzyme Q analogue, on taurochenodeoxycholic acid (TCDC)-induced cell injury and oxidant stress in isolated rat hepatocytes and on glycochenodeoxycholic acid (GCDC)-induced generation of hydroperoxides in fresh hepatic mitochondria. Isolated rat hepatocytes in suspension under 9% oxygen atmosphere were preincubated with 0, 50, and 100 micromol/l idebenone for 30 min and then exposed to 1000 micromol/l TCDC for 4 h. LDH release (cell injury) and thiobarbituric acid reactive substances (measure of lipid peroxidation) increased after TCDC exposure but were markedly suppressed by idebenone pretreatment. In a second set of experiments, the addition of 100 micromol/l idebenone up to 3 h after hepatocytes were exposed to 1000 micromol/l TCDC resulted in abrogation of subsequent cell injury and markedly reduced oxidant damage to hepatocytes. Chenodeoxycholic acid concentrations increased to 5.15 nmol/10(6) cells after 2 h and to 7.05 after 4 h of incubation of hepatocytes with 1000 micromol/l TCDC, and did not differ in the presence of idebenone. In freshly isolated rat hepatic mitochondria, when respiration was stimulated by succinate, 10 micromol/l idebenone abrogated the generation of hydroperoxides during a 90-minute exposure to 400 micromol/l GCDC. These data demonstrate that idebenone functions as a potent protective hepatocyte antioxidant during hydrophobic bile acid toxicity, perhaps by reducing generation of oxygen free radicals in mitochondria.

Animals↗

PubMed1986

Naturally occurring conjugated bile acids, measured by high-performance liquid chromatography, in human, dog, and rabbit bile.

The aim of this study was to determine the biliary pattern of conjugated bile acids after stimulation of their enterohepatic circulation. Conjugated bile acids were separated by reversed-phase ion-pair chromatography without prior derivatization. A MicroPak SP-C18-IP-4 column was used as non-polar matrix, and an ionic alkyl compound, tetrabutylammonium phosphate, was added to the mobile phase, which was a mixture of acetonitrile and water. Quantification was made by UV absorption at 210 nm with external standardization. In fourteen human patients with external biliary drainage after papillotomy there was preferential glycine conjugation. The mean values were 36.5% for glycocholic acid, 33% for glycochenodeoxycholic acid, and 10.0% for glycodeoxycholic acid. Only 15.2% of the biliary bile acids were taurine metabolites. Conjugates of ursodeoxycholic acid were below 2.1%. In most cases, conjugated lithocholic acid was not detected. Within 4 h after ingestion of a standardized meal there were no significant changes in the biliary bile acid pattern. In four dogs (beagles), glycine-conjugated bile acids were lacking. The mean values were 74.3% for taurocholic acid, 14.9% for taurodeoxycholic acid, and 5.3% for taurochenodeoxycholic acid. In six rabbits, 87.4% of biliary bile acids was identified as glycodeoxycholic acid and 5.3% as glycocholic acid. In conscious dogs, as well as in rabbits, the stimulation of biliary secretion by cholecystokinin and/or secretin had no effect on the biliary bile acid spectrum. Evidently, there is a difference in the biliary composition of conjugated bile acids between humans, dogs, and rabbits. Because of the different physicochemical behaviour of glycine- and taurine-conjugated bile salts, it seems difficult to compare the therapeutic effect of gallstone dissolution in various species.

Animals↗

PubMed2002

Bile acids mimic oxidative stress induced upregulation of thioredoxin reductase in colon cancer cell lines.

Bile acids have been suggested to play an important role in the etiology of colon and gastric cancer after gastrectomy, but the molecular biology of these effects is poorly understood. We evaluated the effect of different bile acids on human gastric and colon carcinoma cells and identified genes by RNA arbitrarily primed PCR for differential display that are modulated following treatment with hydrophobic bile acids. Thioredoxin reductase (TR) mRNA was upregulated after treatment with taurochenodeoxycholic acid (TCDCA) in St 23132 cells. This raised the question whether deoxycholic acid (DCA) would have regulative effects on TR in HT-29 cells. After an incubation time of 6 h with DCA, TR mRNA expression was increased up to threefold. Ursodeoxycholic acid had no influence on TR mRNA expression. The upregulation of TR after DCA incubation was almost identical to incubation with 12-O-tetradecanoylphorbol-13-acetate. This implies that hydrophobic bile acids mediate oxidative stress in gastrointestinal cancer cells, which was confirmed by measurement of oxidative burst after treatment with DCA. The results suggest that hydrophobic bile acids induce oxidative stress in gastrointestinal cancer resulting in a compensatory upregulation of TR mRNA, one of the key components in the complex anti-oxidant defense system within eukaryotic cells. The activation of at least parts of the redox signaling system is potentially related to the cytotoxicity and the stimulation of the cell death machinery induced by toxic bile acids.

Base Sequence↗

PubMed1989

Purification and characterization of a new hydrolase for conjugated bile acids, chenodeoxycholyltaurine hydrolase, from Bacteroides vulgatus.

A new hydrolase for conjugated bile acids, tentatively named chenodeoxycholyltaurine hydrolase, was purified to homogeneity from Bacteroides vulgatus. This enzyme hydrolyzed taurine-conjugated bile acids but showed no activity toward glycine conjugates. Among the taurine conjugates, taurochenodeoxycholic acid was most effectively hydrolyzed, tauro-beta-muricholic and ursodeoxycholic acids were moderately well hydrolyzed, and cholic and 7 beta-cholic acids were hardly hydrolyzed, suggesting that this enzyme has a specificity for not only the amino acid moiety but also the steroidal moiety. The molecular weight of the enzyme was estimated to be approximately 140,000 by Sephacryl S-300 gel filtration and the subunit molecular weight of the enzyme was 36,000 by SDS-polyacrylamide gel electrophoresis. The optimum pH was in the range of 5.6 to 6.4. The NH2-terminal amino acid sequence of the enzyme was Met-Glu-Arg-Thr-Ile-Thr-Ile-Gln-Gln-Ile-Lys-Asp-Ala-Ala-Gln. The enzyme was activated by dithiothreitol, but inhibited by sulfhydryl inhibitors, p-hydroxymercuribenzoate, N-ethylmaleimide, and dithiodipyridine.

Amidohydrolases↗