sodium-taurodeoxycholate and Cholelithiasis

The purpose of this study was to demonstrate the aberrant metabolism of bile acids in patients with cholesterol gallstone and explore for its underlying mechanisms. The composition of bile acids collected from the patients with cholelithiasis and the control individuals was analyzed by LC-MS. The expression of genes regulating the metabolism of bile acids was quantitatively determined by real-time PCR or Western blot analysis. Cholesterol saturation index of patients with gallstone was significantly higher than that of the controls. The concentrations of taurodeoxycholic acid and taurolithocholic acid in the bile of patients were significantly higher than that of the controls. When compared with the controls, it was remarkable in the patients that the mRNA expression of farnesoid X receptor (FXR) was lower, whereas that of organic anion transporting polypeptide (OATP1A2) was higher. However, the expressions of both mRNA and protein of cytochrome

Topics: Adult; Bile Acids and Salts; Cholelithiasis; Cholesterol; Female; Humans; Male; Middle Aged; Organic Anion Transporters; RNA-Binding Proteins; RNA, Messenger; Steroid 12-alpha-Hydroxylase; Taurodeoxycholic Acid; Taurolithocholic Acid

The hydrophilic bile salt ursodeoxycholate is frequently used to dissolve cholesterol gallstones. We have now quantitated crystallization as a function of bile salt hydrophobicity, phospholipid content, cholesterol saturation and total lipid concentration (TLCo).. Crystallization in supersaturated model biles with low phospholipid contents (left two-phase-micelles and crystal-containing-zone) was assessed during 21 days by microscopy and chemical measurement of crystal mass. For model biles with higher phospholipid contents (central three-phase-micelles, vesicles and crystal-containing-zone), lipid distribution into various phases was determined by combined ultracentrifugation-filtration-dialysis methodology (Biochim. Biophys. Acta 1532 (2001) 15-27).. In the left two-phase zone, crystal numbers and masses were highest in case of more hydrophilic bile salt composition (TUDC 100%>TC/TUDC 70%/30%>TC 100%>TC/TDC 70%/30%>TDC 100%) and decreased with increasing phospholipid contents, lower TLCo and lower cholesterol saturation index (CSI). In contrast, in the presence of vesicles (three-phase zone), crystallization decreased at increasing bile salt hydrophilicity, with concomitant increased vesicular cholesterol solubilization.. Presence of vesicular phases is a prerequisite for inhibition of cholesterol crystallization by tauroursodeoxycholate.

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Hydrophobic and Hydrophilic Interactions; Micelles; Phosphatidylcholines; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid

Acute pancreatitis is associated with passage of gallstones, although the mechanism(s) linking the two processes remains undefined. Bile reflux into the pancreatic duct could play a role but the experimental conditions often employed to induce pancreatitis rarely develop clinically. Here we examined whether low concentrations of bile affect ductal electrophysiology as an indirect measure of ductal epithelial integrity and function in vitro.. The main duct was dissected out of freshly harvested bovine pancreata, cut into 1- x 2-cm sections, placed in tissue culture for 48-72 h, then placed in Ussing chambers. Changes in tissue resistance (Rt) and short-circuit current (Isc) were monitored. The responses to forskolin and bile (taurodeoxycholic acid, TDCA) were examined separately and together.. Forskolin (10 microM) produced a decrease in the Isc without a significant change in Rt, suggesting a secretory response, followed by a return to baseline. TDCA caused a similarly reversible decrease in the Isc at low doses, but a persistent drop at higher concentrations. A concurrent drop in Rt was noted at all TDCA concentrations, the duration of which correlated with dosage and degree of histological damage. Prior exposure to low (0.5 mM) doses of TDCA significantly blunted the response to subsequent forskolin challenge.. Acute exposure to TDCA in vitro causes epithelial damage at levels lower than those normally used to induce experimental pancreatitis. At the lower concentrations, Rt returns to baseline rapidly, suggesting recovery (restitution) from epithelial damage but with a persistent loss of the response to forskolin. Reflux of minute amounts of bile into the pancreatic duct could play a significant role in the pathogenesis of gallstone pancreatitis by uncoupling the normal stimulus-secretion apparatus of the ductal system and breaking down the epithelial barrier.

Topics: Acute Disease; Animals; Bile Acids and Salts; Cattle; Cholelithiasis; Colforsin; Dose-Response Relationship, Drug; Electrophysiology; Epithelium; Humans; In Vitro Techniques; Pancreatic Ducts; Pancreatitis; Taurodeoxycholic Acid

Dietary cholesterol (CHL) and triglycerides (TG) can influence plasma, hepatic, and biliary lipid composition, but effects on lipids in these three compartments during the early stages of CHL gallstone formation have not been studied in parallel. We fed prairie dogs diets containing one of four test oils (safflower, coconut, olive, or menhaden) at either 5 or 40% of calories, in the presence of 0 or 0.34% CHL, for 3 wk. In the absence of dietary CHL, increases in dietary TG produced 50-200% increases in the concentrations of biliary CHL and hepatic cholesteryl ester (CE), while the concentrations of hepatic free CHL (FC) as well as plasma FC and CE remained relatively unchanged. Increasing dietary CHL to 0.34% resulted in increases in hepatic FC of approximately 50% for all four fats regardless of whether they were supplied at 5 or 40% of calories. CHL supplementation caused more pronounced increases in biliary CHL (200-400%), hepatic CE (50-200%), plasma FC (up to 100%), and plasma CE (up to 150%), and these increases were exacerbated by concurrent supplementation of dietary fat and CHL (biliary CHL: 300-700%; hepatic CE: 100-250%; plasma FC: up to 165%; plasma CE: 100-350%). These results indicate that enhanced secretion of biliary CHL and, to a lesser extent, increased synthesis of hepatic CE, may be primary mechanisms for maintaining the hepatic FC pool. Furthermore, dietary CHL and high levels of fat intake are independent risk factors for increasing biliary CHL concentrations, and adverse effects on lipid concentrations in plasma and bile tend to be exacerbated by ingestion of diets rich in both fat and CHL.

Topics: Animals; Bile; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Dietary Fats; Female; Liver; Phospholipids; Sciuridae; Taurocholic Acid; Taurodeoxycholic Acid; Triglycerides

To assess whether the presence in bile of HMG-CoA reductase inhibitors, which are secreted predominantly into the bile, influences biliary lithogenicity.. Physiologic biliary concentrations of the hydrophilic HMG-CoA reductase inhibitor pravastatin were added to supersaturated model bile (cholesterol saturation index 1.4) and vesicles, the latter with and without the concomitant addition of the nucleation-promoting bile salt taurodeoxycholate.. Nucleation time, defined as the number of days after which cholesterol monohydrate crystals are visible by phase contrast microscopy in filtered samples of model bile and vesicles, was assessed.. The addition of pravastatin 0.01-1 mg/ml did not influence the nucleation time of supersaturated model bile (mean nucleation time without pravastatin: 8.3 +/- 2.2 days (SD), with pravastatin 1 mg/ml 9.3 +/- 0.4 days and pravastatin 0.01 mg/ml 7.6 +/- 2.3 days). The addition of similar concentrations of pravastatin to vesicle fractions alone did not influence nucleation time (> 20 days), nor could it prevent the nucleation-promoting effect of taurodeoxycholate (nucleation time with or without pravastatin 1 day).. The results from this in-vitro study indicate that the presence of pravastatin in bile may not influence gallbladder bile lithogenicity. It can be hypothesized that this also applies to other HMG-CoA reductase inhibitors.

Topics: Anticholesteremic Agents; Bile; Cholagogues and Choleretics; Cholelithiasis; Cholesterol; Crystallization; Drug Interactions; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Microscopy, Phase-Contrast; Pravastatin; Taurodeoxycholic Acid; Time Factors

Precipitation of cholesterol crystals is an essential step in gallstone formation. In the present study we found much faster and more extensive precipitation of various cholesterol crystal shapes in whole model biles containing the hydrophobic bile salt taurodeoxycholate than in biles containing the relatively hydrophilic taurocholate. Addition of taurodeoxycholate to isolated cholesterol-phospholipid vesicles also induced more crystallization than taurocholate. Crystallization behaviour in whole model biles and in vesicles after addition of corresponding bile salts was very similar. The very hydrophilic bile salts tauroursodeoxycholate and taurohyodeoxycholate never induced crystallization from vesicles, and crystallization in corresponding whole model biles did not occur. These bile salts also reduced crystallization dose dependently after addition of taurodeoxycholate to vesicles. Ultracentrifugation experiments suggested a higher vesicular cholesterol-phospholipid bile salts. These findings indicate that bile salt hydrophobicity influences shape of cholesterol crystals and extent of crystallization, possibly by modulating the vesicular cholesterol-phospholipid ratio.

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Humans; In Vitro Techniques; Models, Biological; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid

Glycine-conjugated, dihydroxy bile salts inhibit calcium hydroxyapatite (HAP) formation by binding to and poisoning nascent crystal embryos. Their taurine-conjugated counterparts bind less well to hydroxyapatite and do not inhibit its formation; but more hydrophobic, synthetic analogs of the taurine conjugated bile salts are inhibitors of hydroxyapatite formation. Because hydrophobicity is an important determinant of the ability of bile salts to inhibit hydroxyapatite crystal growth, experiments were performed to study the effect of the physiologically important mixed micelles of bile salt and phospholipid. Taurodeoxycholate/phosphatidylcholine (10:1) mixed micelles bound to HAP at lower total lipid concentrations than did pure taurodeoxycholate. At low total lipid concentrations, phosphatidylcholine (PC) binding appeared to predominate, suggesting that PC had a higher affinity than did taurodeoxycholate (TDC) for the HAP surface. Although glycodeoxycholate (3 mM) significantly (> 95%) inhibited hydroxyapatite precipitation, higher concentrations of taurodeoxycholate, either alone or mixed with phosphatidylcholine, did not affect hydroxyapatite formation. These results suggest that biliary phospholipids do not modulate the ability of bile salts to inhibit hydroxyapatite crystal growth.

Topics: Bile; Bile Acids and Salts; Binding Sites; Cholelithiasis; Crystallization; Durapatite; Humans; In Vitro Techniques; Micelles; Phosphatidylcholines; Phospholipids; Spectrometry, Fluorescence; Taurodeoxycholic Acid

Because an increase in biliary deoxycholate levels seems to be a risk factor for cholesterol gallstone formation, we determined the relationship between deoxycholate levels and levels of the pronucleating protein, immunoglobulin G (Ig) in human gallbladder bile. Patients with cholesterol gallstones had a higher concentration of biliary IgG compared with a pigmented stone group and control patients. This was associated with the simultaneous presence of two conditions in the cholesterol stone group, supersaturated bile and a high deoxycholate/cholate ratio. The other patient groups met only one of the two conditions. Next, animal studies were performed to determine if model biles mimicking the two conditions could affect IgG secretion by the gallbladder. Gallbladders were exposed in vivo and then in an Ussing chamber to model biles. The voltage clamp technique was used to monitor functional integrity of the preparation. Three different model biles were tested: (1) taurodeoxycholate (TDC), 80%; taurocholate (TC), 20%; and cholesterol saturation index (CSI), 1.2; (2) TDC, 20%; TC, 80%; and CSI, 1.2; and (3) TDC, 80%; TC, 20%; and CSI, 0.6. IgG concentrations became significantly higher in group 1 than in the other two groups. The concentration of mucous glycoprotein was also significantly greater in group 1 when compared with group 2. Plasma cells were increased in number in mucosal and submucosal layers in group 1. We conclude that cholesterol supersaturated model bile with high content of TDC induces gallbladder epithelial alterations, which increase the luminal concentration of IgG and mucous glycoprotein.

Topics: Animals; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Glycoproteins; Humans; Immunoglobulin G; Osmolar Concentration; Pigmentation; Reference Values; Swine; Taurocholic Acid; Taurodeoxycholic Acid

Unconjugated bile salts currently available for gallstone dissolution are poorly effective. We evaluated in vitro the litholytic potency of taurine-amidated bile salts against human cholesterol gallstones.. Seventy radiolucent gallstones with similar size and composition (cholesterol content, 70.1 +/- 0.9%) from a single patient were incubated in model biles composed of 100 mM of either taurochenodeoxycholate (TCDC), taurocholate (TC), taurohyodeoxycholate (THDC) or tauroursodeoxycholate (TUDC) and of 45 mM egg yolk lecithin in saline buffered with tris/HCl (at pHs 7 and 8) or phosphate (at pHs 4 and 6). Biles (total lipids, 10 g/dl; cholesterol saturation, 99%) were incubated at 37 degrees C for 40 days. Gallstones were periodically weighed and returned to the dissolution vials, and the biliary cholesterol concentration was monitored.. Model biles remained optically clear during the initial 48 h of incubation. Then, biles containing THDC and TUDC, but not those with TC and TCDC, became progressively turbid until, after several days, a white precipitate surrounded the residual stone. Abundant liquid crytalline droplets were observed at polarizing microscopy in biles containing TUDC and THDC. Gallstone dissolution was closely related to cholesterol solubilization and decreased in the order TCDC > THDC > or = TC > TUDC, being highest at pH 8. At the physiologic pH of 7 THDC was more litholythic than TC.. In vitro, the litholytic potency of bile salts on cholesterol gallstones primarily depends on their hydrophobicity. THDC is a new potential gallstone-dissolving agent, deserving in vivo studies.

Topics: Cholagogues and Choleretics; Cholelithiasis; Cholesterol; Drug Combinations; Drug Evaluation, Preclinical; Humans; Hydrogen-Ion Concentration; Phosphatidylcholines; Taurochenodeoxycholic Acid; Taurodeoxycholic Acid

In this study we investigated the anticholelithogenic and choleretic activities and the general pharmacological action of taurohyodeoxycholic acid (THDCA, Io, Praxis, CAS 2958-04-5), a new biliary acid advocated for use as anticholelithogenic agent. THDCA had no significant activity on the CNS (spontaneous locomotor activity, body temperature, coordinated movement, respiration); it also had no significant anticonvulsant or central anticholinergic actions. With regard to the action on the cardiovascular system, THDCA administration did not give rise to significant changes in blood pressure or ECG. Investigation of its action on the gastrointestinal system revealed no significant changes in the intestinal transport of charcoal after treatment. However, biliary flow and biliary solids content were increased by THDCA intraduodenal doses of 300 mg/kg b.w. In mice fed with lithogenic diet THDCA administration (230 and 450 mg/kg b.w. for 8 weeks) significantly decreased gallstone and steatosis incidence.

Topics: Animals; Biliary Tract; Central Nervous System; Cholagogues and Choleretics; Cholelithiasis; Digestive System; Female; Guinea Pigs; Hemodynamics; Male; Mice; Rabbits; Rats; Rats, Sprague-Dawley; Respiratory System; Steatitis; Taurodeoxycholic Acid; Ursodeoxycholic Acid

The possible role of conjugated bile salts in the induction and mediation of acute aseptic cholecystitis has been assessed. Using an experimental model, we determined the passive permeability to fluorescently labelled dextran in the gallbladder wall when exposed to different bile salts, alone or together with lecithin. Both taurocholate (20 mM) and, in particular, taurodeoxycholate (20 mM) markedly increased the transmural passage of dextran, but this effect was inhibited by lecithin (50 mM). Bile from patients with cholesterol gallstones contained relatively more deoxycholates (19.4% +/- 8.6%) and less lecithin (35 +/- 20 mmol/l) than did bile from patients with uncomplicated gastric disease (14.1 +/- 6.0% deoxycholates and 53 +/- 26 mmol lecithin/l). Since deoxycholates are more inflammation-promoting than cholates in several systems, and lecithin is considered necessary for protection against the devastating effects of bile salts, these findings should not be overlooked in current hypotheses on the pathogenesis of acute calculous cholecystitis.

Topics: Adult; Animals; Bile Acids and Salts; Cholecystitis; Cholelithiasis; Chromatography; Female; Gallbladder; Humans; Male; Middle Aged; Models, Biological; Permeability; Phosphatidylcholines; Rabbits; Taurocholic Acid; Taurodeoxycholic Acid