SEARCH · PubMed Health

Results for “Taurochenodeoxycholic Acid”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed2002

Effects of bile acids on the muscle functions of guinea pig gallbladder.

Hydrophobic bile acids impair gallbladder emptying in vivo and inhibit gallbladder muscle contraction in response to CCK-8 in vitro. This study was aimed at determining the mechanisms of muscle cell dysfunction caused by bile acids in guinea pig gallbladders. Muscle cells were obtained by enzymatic digestion. Taurochenodeoxycholic acid (TCDC), a hydrophobic bile acid, caused a contraction of up to 15% and blocked CCK-induced contraction. Indomethacin abolished the TCDC-induced contraction. Hydrophilic bile acid tauroursodeoxycholic acid (TUDC) had no effect on muscle contraction but prevented the TCDC-induced contraction and its inhibition on CCK-induced contraction. Pretreatment with NADPH oxidase inhibitor PH2I, xanthine oxidase inhibitor allopurinol, and free-radical scavenger catalase also prevented TCDC-induced contraction and its inhibition of the CCK-induced contraction. TCDC caused H2O2 production, lipid peroxidation, and increased PGE2 synthesis and activities of catalase and SOD. These changes were significantly inhibited by pretreatment of PH2I or allopurinol. Inhibitors of cytosolic phospholipase A2 (cPLA2), protein kinase C (PKC), and mitogen-activating protein kinase (MAPK) also blocked the TCDC-induced contraction. It is concluded that hydrophobic bile acids cause muscle cell dysfunction by stimulating the formation of H2O2 via activation of NADPH and xanthine oxidase. H2O2 causes lipid peroxidation and activates cPLA2 to increase PGE2 production, which, in turn, stimulates the synthesis of free-radical scavengers through the PKC-MAPK pathway.

Animals↗

PubMed2006

Chenodeoxycholic acid and taurochenodexycholic acid induce anti-apoptotic cIAP-1 expression in human hepatocytes.

BACKGROUND AND AIMS: Increased concentration of endogenous bile acids in the liver correlates with clinical features of cholestatic liver diseases. Recently, it was reported that non-toxic hydrophobic bile acid activated a survival signaling pathway via phosphatidylinositol 3 (PI3) kinase in hepatocytes. However, whether bile acid induces inhibitors of apoptosis protein (IAPs) directly in human hepatocytes remains unknown. This study investigated effects of bile acids on cIAP-1, cIAP-2 and XIAP expression in hepatocytes. METHODS: Human fetal hepatocytes and HepG2 cells were treated with free or conjugated chenodeoxycholic acid (CDCA) or ursodeoxycholic acid in the presence or absence of several inhibitors. Reverse transcriptase-polymerase chain reaction and Western blot analyses were performed for mRNA and protein expressions, respectively, of IAPs. Luciferase assay was used to investigate transcriptional activity of nuclear factor (NF)-kappaB. RESULTS: Chenodeoxycholic acid up-regulated both mRNA and protein expressions of cIAP-1. In particular, taurochenodeoxycholic acid (TCDCA), but not glycochenodeoxycholic acid (GCDCA), induced cIAP-1 mRNA expression. In contrast, cIAP-2 and XIAP mRNA expressions were not influenced by CDCA. Moreover, CDCA-induced cIAP-1 mRNA expression was inhibited completely by calphostin C and SB203580, but not by wortmannin. Luciferase assay showed that CDCA and TCDCA activated NF-kappaB-driven transcriptional activity. CONCLUSION: It was shown that CDCA induced cIAP-1 expression in hepatocytes through protein kinase C- and p38 mitogen-activated protein kinase-mediated pathway. Especially, TCDCA, but not GCDCA, increased cIAP-1 mRNA expression and NF-kappaB-regulated transcriptional activity. Therefore, it is suggested that CDCA and TCDCA themselves have an inhibitory potential against apoptosis through the cIAP-1-survival signaling pathway, in addition to PI3 kinase-dependent pathway.

Apoptosis↗

PubMed1977

Partial purification and characterization of NAD-dependent 7alpha-hydroxysteroid dehydrogenase from Bacteroides thetaiotaomicron.

A NAD-dependent 7alpha-hydroxysteroid dehydrogenase was purified 18-fold over the activity in crude cell extracts prepared from Bacteroides thetaiotaomicron NCTC 10852 using Bio-Gel A 1.5-M column chromatography. A molecular weight of 320 000 was estimated for the partially purified intact enzyme. Substrate saturation kinetics were performed using the 18-fold purified enzyme and the lowest Km values were obtained for 3alpha,7alpha-dihydroxy bile acid and bile salt substrates including chenodeoxycholic acid (Km 0.048 mM), glycochenodeoxycholic acid (Km 0.083 mM) and taurochenodeoxycholic acid (Km 0.059 mM). In contrast, 3alpha,7alpha,12alpha-trihydroxy bile acid and bile salts had higher Km values, i.e. cholic acid (Km 0.22 mM), glycoholic acid Km 0.32 mM) and taurocholic acid Km 0.26 mM). NAD had a Km value of 0.20 mM. The possible physiological significance of 7alpha-hydroxy bile acid oxidation to intestinal bacteroides strains was accessed by determining the rate of conversion of [14C]-cholic acid to 7-ketodeoxy[14C]cholic acid by whole cell suspensions under different incubation conditions. The rate of biotransformation of bile acid to keto-bile acid incubated anaerobically under N2 gas increased markedly when potential electron acceptors such as fumarate (10 mM) or menadione (4 mM) was added exogenously. These results suggest that bile acid oxidation reactions may be linked to energy-generating systems in this bacterium.

Bacteroides↗

PubMed1995

Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids.

BACKGROUND & AIMS: The mechanisms causing liver injury in cholestatic diseases are unclear. The hypothesis that accumulation of hydrophobic bile acids in hepatocytes during cholestasis leads to generation of oxygen free radicals and oxidative injury was tested. The aim of this study was to determine if hydrophobic bile acid toxicity is associated with increased hydroperoxide generation in isolated rat hepatocytes and mitochondria. METHODS: Hepatocytes were exposed to taurochenodeoxycholic acid (TCDC; 0-2000 mumol/L) or taurocholic acid (TC; 1000 mumol/L), and cellular injury, intracellular hydroperoxide generation, and thiobarbituric acid-reacting substances (TBARS) were measured. Isolated mitochondria were incubated with 400 mumol/L chenodeoxycholic acid or 400 mumol/L cholic acid, and hydroperoxide generation was measured fluorometrically. RESULTS: Hepatocyte injury, hydroperoxide generation, and TBARS increased over 4 hours on exposure to TCDC but not TC. Hydroperoxide generation preceded hepatocyte injury and accumulation of TBARS. Preincubation of hepatocytes with the antioxidant, d-alpha-tocopheryl succinate, completely abrogated cellular injury, hydroperoxide, and TBARS generation. Hydroperoxide generation was increased in mitochondria exposed to chenodeoxycholic acid. CONCLUSIONS: Intracellular generation of hydroperoxides by mitochondria appears to be an early event in hydrophobic bile acid-induced hepatocyte toxicity. Antioxidants may be of benefit in cholestasis.

Animals↗

PubMedDate not supplied

Effect of increased bile flow and bile acid secretion on the hepatic elimination of sodium valproate in the cat.

The effect of increased bile flow and hepatic bile acid flux on the systemic clearance and hepatic elimination of intravenously administered sodium valproate was studied in the bile fistula cat. Taurochenodeoxycholic acid (TCDC), tauro-3 alpha, 7 beta-dihydroxy-12-keto-5 beta-cholanoic acid (T12K), SC-2644, and secretin were infused intravenously to vary bile flow and biliary bile acid secretion. Control animals were infused with 0.15 mol/l NaCl. Less than 1% of the drug administered to controls appeared as unchanged valproate in the bile over 6 h. Although SC-2644, T12K, and secretin significantly increased biliary excretion of valproate, it did not exceed 2% of the intravenous dose. Biliary clearance was directly related to the rate of bile flow, but not to the bile acid flux. By contrast, 18-19% of the dose appeared in bile as metabolite in controls, and none of the choleretic agents significantly increased this percentage. As a result, systemic clearance of valproate was unaltered. We conclude that the movement of unchanged valproate into bile is consistent with a process of simple diffusion. The fact that choleretic agents do not increase metabolite excretion into bile suggests that metabolite formation may be the rate-limiting step in the hepatic elimination of valproate, rather than transport and excretion of metabolites into bile.

Animals↗

PubMed1992

Substrate-specific differences in the rate of bile acid carrier reorientation: studies on human placental basal vesicles.

The initial rate of transport of the bile acid glycocholic acid (GCA) has been measured in influx and efflux across placental basal membrane vesicles, and the mechanism of inhibition of its transport by the analogue taurochenodeoxycholic acid (TCDCA) analysed kinetically. This analogue, although trans-stimulating GCA efflux, inhibits influx in a way which does not depend upon substrate concentration; moreover, its potency as an inhibitor is markedly influenced by whether it is placed on one or on both sides of the vesicles membrane. These findings can be accounted for by postulating that both GCA and TCDCA are translocated through the carrier, but that the rate of loaded carrier reorientation is higher than that of the free carrier only when loaded with TCDCA and not with GCA.

Bile Acids and Salts↗

PubMed1994

Tubulovesicular transport of horseradish peroxidase in isolated rat hepatocyte couplets: effects of low temperature, cytochalasin B and bile acids.

The transcytotic vesicular pathway in isolated rat hepatocyte couplets was investigated using horseradish peroxidase. Ten to 20 min after horseradish peroxidase labeling, vesicles and tubules containing horseradish peroxidase were observed to be predominantly around the bile canaliculi. In hepatocytes incubated in a 4 degrees C medium for 10 min after horseradish peroxidase labeling, few horseradish peroxidase-containing structures were observed around the bile canaliculi, and the fine reticular immunofluorescence of microtubules was reduced. Cells treated with cytochalasin B (a microfilament inhibitor) showed a fair number of horseradish peroxidase-containing structures around the markedly dilated bile canaliculi and the distribution of microtubules was preserved. Cells labeled by horseradish peroxidase and then incubated for 10 min in a horseradish peroxidase-free medium containing 50 mumol/L of taurocholic acid, ursodeoxycholic acid or tauroursodeoxycholic acid had more tubular structures containing horseradish peroxidase around the bile canaliculi than control cells, whereas 50 mumol/L of taurochenodeoxycholic acid, taurodeoxycholic acid, dehydrocholic acid and taurodehydrocholic acid each failed to increase the number of tubular structures. These findings show that horseradish peroxidase was transported in hepatocyte couplets from the cell periphery to the bile canalicular front through the tubulovesicular pathway, depending on cytoplasmic microtubules. Cytoplasmic microfilaments appeared to play a minor role in this transport. Several specific bile acids such as taurocholic acid, ursodeoxycholic acid and tauroursodeoxycholic acid each promoted the tubular transformation.

Animals↗

PubMed1994

Dietary fish oil potentiates bile acid-induced cholesterol secretion into bile in rats.

Recently we demonstrated that dietary fish oil (FO) causes changes in intrahepatic cholesterol transport and hypersecretion of cholesterol into bile in rats (J. Clin. Invest. 88: 943-951, 1991). We have now investigated in more detail the relationship between cholesterol and bile acid secretion in rats with chronic bile diversion fed purified diets supplemented (9% wt/wt) with either FO or corn oil (CO) for 2 weeks. Effects of FO on biliary cholesterol secretion (+ 400% as compared to CO after 14 days) were much more pronounced than previously observed in rats with intact enterohepatic circulation (+50%). Biliary bile acid (+30%) and phospholipid (+120%) secretion were increased to a much lesser extent than that of cholesterol resulting in the formation of bile supersaturated with cholesterol. The biliary cholesterol/bile acid molar ratio was 0.069 and 0.032 in FO- and CO-fed rats, respectively, at noon of day 14. This ratio increased to 0.108 in FO-fed rats at midnight, when bile acid output was maximal, but remained unchanged in CO-fed rats during the day-night cycle. Intravenous administration of taurochenodeoxycholic acid (15 mumol/kg) resulted in a 2-fold increase in bile acid output and a simultaneous 1.6-fold stimulation of cholesterol secretion in both groups, implying that administration of the bile acid induced the secretion of 2-3 times as much cholesterol in FO- than in CO-fed rats. Likewise, administration of bilirubin ditaurate (30 mumol/kg), an inhibitor of bile acid-induced biliary lipid secretion, reduced cholesterol output in both groups by about 50% while bile acid output remained unchanged. It is concluded that, in rats, dietary fish oil increases the disposition of cholesterol into bile by potentiating bile acid-dependent cholesterol secretion, presumably by facilitating the recruitment of bile-destined cholesterol.

Animals↗

PubMed1993

Effects of dibutyryl cyclic AMP and papaverine on intrahepatocytic bile acid transport. Role of vesicle transport.

The secondary messenger cyclic AMP plays an important role in regulating biliary excretory function by stimulating the transcytotic vesicle transport system, whereas papaverine exerts an inhibitory effect on this system. We therefore investigated their effects on bile acid-induced cytotoxicity and intrahepatocytic content of bile acid in primary cultured rat hepatocytes. Simultaneous addition of 1 mM dibutyryl cyclic AMP (DBcAMP), an analogue of cAMP, with 1 mM taurochenodeoxycholic acid (TCDCA) significantly decreased the release of lactate dehydrogenase (LDH) as compared with the case with 1 mM TCDCA alone (7.1 +/- 0.13% of total versus 10.7 +/- 0.3%). In contrast, 0.1 mM papaverine approximately doubled the amount of LDH (22.0 +/- 0.6% of total versus 10.7 +/- 0.3%; P < 0.01). The intracellular content of TCDCA 180 min after the administration of 1 mM TCDCA alone was 20.8 +/- 0.7 nmol/mg protein, that after simultaneous administration of 1 mM DBcAMP, 16.2 +/- 1.0 nmol/mg protein, and that after the simultaneous administration of 0.1 mM papaverine, 38.5 +/- 1.9 nmol/mg protein. A clear correlation between the release of LDH from hepatocytes and the intracellular content of TCDCA was thus observed. When given together with 1 mM taurocholic acid (TCA) or 1 mM tauroursodeoxycholic acid (TUDCA), papaverine exerted little effect on cytotoxicity or intrahepatocytic bile acid content. When cells were bathed in a medium free of bile acid after pretreatment with 1 mM TCDCA and 1 mM DBcAMP, additional exposure to DBcAMP for 30 min significantly stimulated reduction of intracellular TCDCA content (30.2 +/- 0.4% of total versus 44.0 +/- 1.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Effect of bile salts on oviposition in vitro by Schistosoma mansoni.

Adult pairs of Schistosoma mansoni were kept in culture in the presence or absence of various bile salts and the numbers of parasite eggs deposited in vitro were monitored for 2 weeks. The hydrophilic bile salt tauroursodeoxycholic acid (TUDCA) was found to produce a highly significant increase in the number of eggs deposited during the 1st week of culture. The hydrophobic bile salt taurochenodeoxycholic acid (TCDCA) and the intermediately hydrophobic salt taurocholate (TCA) produced more moderate increases. These results expand previous data showing that schistosomes kept in the presence of portal blood have higher oviposition rates than schistosomes kept in systemic blood.

Animals↗

PubMed1994

Biliary lipid composition in heterozygous familial hypercholesterolemia and influence of treatment with probucol.

The lipid composition of fasting duodenal bile was determined in 11 healthy subjects with normolipidemia and 15 patients with heterozygous familial hypercholesterolemia (FH) (12 with type IIa, three with type IIb). The age distribution among the groups of subjects was similar. In the patients with heterozygous FH type IIa, the mean value for molar percentage of cholesterol and lithogenic index (LI) of bile were significantly higher than those of controls (8.4 +/- 1.0%, 1.47 +/- 0.18 calculated by Hegard, Dam, and Holzbach vs 4.3 +/- 0.4%, 0.81 +/- 0.07, respectively). The value of LI in the patients with FH type IIb was also found to be significantly higher than that of the controls. In the patients with heterozygous FH type IIa, we observed both a significant decrease in the molar percentages of glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycolithocholic acid, and a significant increase of taurochenodeoxycholic acid compared to the corresponding values in the controls. Bile analysis of six patients was reexamined during probucol treatment after 16 weeks. Probucol significantly lowered serum cholesterol levels. However, biliary lipid composition and individual bile acid proportions was not altered by the treatment. The results suggest that most of the patients with heterozygous FH have supersaturated bile and are predisposed to cholesterol gallstone formation. In addition, the mechanism by which probucol lowers serum cholesterol appears to be independent of any change in the metabolism of biliary lipid.

Adult↗

PubMed1987

Effects of ursodeoxycholic acid, analogues of ursodeoxycholic acid and combination of bile acids on bile acid synthesis in cultured rat hepatocytes.

The effect of individual 7 beta-hydroxy bile acids (ursodeoxycholic and ursocholic acid), bile acid analogues of ursodeoxycholic acid, combination of bile acids (taurochenodeoxycholate and taurocholate), and mixtures of bile acids, phospholipids and cholesterol in proportions found in rat bile, on bile acids synthesis was studied in cultured rat hepatocytes. Individual steroids tested included ursodeoxycholate (UDCA), ursocholate (UCA), glycoursodeoxycholate (GUDCA) and tauroursodeoxycholate (TUDCA). Analogues of UDCA (7-methylursodeoxycholate, sarcosylursodeoxycholate and ursooxazoline) and allochenodeoxycholate, a representative of 5 alpha-cholanoic bile acid were also tested in order to determine the specificity of the bile acid biofeedback. Each individual steroid was added to the culture media at concentrations ranging from 10 to 200 microM. Mixtures of taurochenodeoxycholate (TDCA) and taurocholate in concentrations ranging from 150 to 600 microM alone and in combination with phosphatidylcholine (10-125 microM) and cholesterol (3-13 microM) were also tested for their effects on bile acid synthesis. Rates of bile acid synthesis were determined as the conversion of added lipoprotein [4-14C]cholesterol or [2-14C]mevalonate into 14C-labeled bile acids and by GLC quantitation of bile acids secreted into the culture media. Individual bile acids, bile acid analogues, combination of bile acids and mixture of bile acids with phosphatidylcholine and cholesterol failed to inhibit bile acid synthesis in cultured hepatocytes. The addition of UDCA or UCA to the culture medium resulted in a marked increase in the intracellular level of both bile acids, and in the case of UDCA there was a 4-fold increase in beta-muricholate. These results demonstrate effective uptake and metabolism of these bile acids by the rat hepatocytes. UDCA, UCA, TUDCA and GUDCA also failed to inhibit cholesterol-7 alpha-hydroxylase activity in microsomes prepared from cholestyramine-fed rats. The current data confirm and extend our previous observations that, under conditions employed, neither single bile acid nor a mixture of bile acids with or without phosphatidylcholine and cholesterol inhibits bile acid synthesis in primary rat hepatocyte cultures. We postulate that mechanisms other than a direct effect of bile acids on cholesterol-7 alpha-hydroxylase might play a role in the regulation of bile acid synthesis.

Animals↗

PubMed1990

Tauroursodeoxycholic acid inhibits the cytosolic Ca++ increase in human neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine.

The effect of the cytoprotective bile acid tauroursodeoxycholic acid (TUDCA) on basal cytosolic free Ca++ (Ca++)i and receptor-mediated (Ca++)i increase was studied in human polymorphonuclear neutrophils using the fluorescent dye quin2. Basal levels of (Ca++)i were 96 +/- 6 nmol/l (mean +/- SEM, n = 48). TUDCA and its cytotoxic epimer taurochenodeoxycholic acid (TCDCA) at 500 mumols/l increased (Ca++)i by 31 +/- 12 and 27 +/- 7 nmol/l, respectively (n = 6, p less than 0.05). Stimulation of neutrophils with the chemotactic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10(-7) mol/l) induced a (Ca++)i increase of 200 +/- 32 nmol/l which was inhibited after preincubation with TUDCA (500 mumols/l) or TUDCA + TCDCA (500 mumols/l, each) by 60.1% and 59.5%, respectively, but not with TCDCA (500 mumols/l) alone. The inhibitory effect of TUDCA on FMLP-induced (Ca++)i increase was strongly concentration-dependent and was nearly complete at 1000 mumols/l. Since (Ca++)i is discussed as a mediator of cellular injury we hypothesize that TUDCA may exert its protective effects at least partly via inhibition of (Ca++)i-mediated cytotoxic processes.

Calcium↗

PubMed1982

[Comparison of commercially available radioimmunoassays for the determination of bile acids in serum (author's transl)].

Three commercially available radioimmunoassays for the determination of bile acids in serum were evaluated with respect to specificity and precision. The SLCG-radioimmunoassay (Abbott) measures chiefly cholic acid conjugates, and the CBA-radioimmunoassay (Becton-Dickinson) measures all conjugated bile acids, with an over-response to taurine metabolites. With respect to cross reactions, the performances of the CG-and the CBA-radioimmunoassays differed significantly from those stated by the manufacturers, the former showing a 32% response to taurocholic acid, the latter responding only 118% to taurochenodeoxycholic acid. At physiological concentrations of albumin + globulin, the recovery of defined cholanic acids was 85-101%. Good reproducibility was shown by the CG-radioimmunoassay in the range 0.5-10.0 mumol/l, by the CBA-radioimmunoassay in the range 1.0-25.0 mumol/l, and by the SLCG-radioimmunoassay in the range 0.5-3.0 mumol/l. There were no important differences in the inter-and intra-assay precision of the three methods.

Antibody Specificity↗

PubMed1996

Synthesis and physicochemical, biological, and pharmacological properties of new bile acids amidated with cyclic amino acids.

New analogs of cyclic amino acid-conjugated bile acids were synthesized, and their physicochemical and biological properties were compared with those of natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids were amidated with L-proline. The physicochemical properties were similar to those of the natural analogs. All of them were highly stable toward enzymatic C-24 amide bond hydrolysis and 7-dehydroxylation. Their transport, metabolism, and effect on biliary lipid secretion were evaluated in bile fistula rat after intravenous infusion. All the analogs were secreted in bile unmodified. The 4-methoxy-L-proline derivative produced the highest secretion rate, much higher than those of all the other natural and synthetic analogs. This was associated with a selective reduction of cholesterol secretion with normal phospholipid secretion and choleresis. When coinfused, all the analogs were able to prevent the hepatotoxicity induced by intravenous taurochenodeoxycholic acid, as revealed by normal choleresis, alkaline phosphatase, and lactate dehydrogenase values in bile. Considering the overall data, 4-methoxy-L-proline, 4-hydroxy-L-proline, and L-proline derivatives of ursodeoxycholic acid were more potent than the natural analogs.

Amides↗

PubMed1993

Mechanism of bile acid-induced biliary lipid secretion in the rat: effect of conjugated bilirubin.

We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid and cholesterol secretion in unanesthetized normal Wistar (NW) and Groningen Yellow (GY) Wistar rats under various experimental conditions. GY rats express a genetic defect in biliary secretion, but not in hepatic uptake, of various organic anions. Under physiological conditions, NW and GY rats showed similar biliary secretion rates of bile acids and of bilirubin, despite the fact that bilirubin concentrations in GY plasma were 25 times as high and in GY livers three times as high as in NW plasma and livers, respectively. Secretion of cholesterol and phospholipids was not impaired in GY rats under these conditions. Biliary secretion of intravenously injected BDT (3 mumol/100 g body wt) was delayed in eight-day bile-diverted GY rats and showed lower peak values when compared with NW rats. The inhibitory effects of BDT on phospholipid and cholesterol secretion paralleled these differences, being delayed and much less pronounced in GY rats. No overshoot in phospholipid or cholesterol secretion was observed when bilirubin output returned to preinjection values. Stimulation of [14C]choline-labeled phospholipid secretion after a bolus injection of taurochenodeoxycholic acid (1 mumol/100 g body wt) closely followed biliary bile acid concentration. Similarly, inhibition of labeled phospholipid secretion by BDT closely paralleled the biliary bilirubin concentration. Gel filtration studies (Sepharose 4B-CL) under micelle-preserving conditions demonstrated a specific interaction of BDT with biliary bile acids. The presented data indicate that conjugated bilirubin does not inhibit biliary lipid secretion via interaction with bile acids inside the hepatocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis.

To assess the effects of tauroursodeoxycholic acid (TUDCA) on bile excretory function, we examined whether TUDCA modulates vesicular exocytosis in the isolated perfused liver of normal rats in the presence of high (1.9 mM) or low (0.19 mM) extracellular Ca++ and in cholestatic rats 24 h after bile duct ligation. In addition, the effects of TUDCA on Ca++ homeostasis were compared in normal and in cholestatic hepatocytes. In the isolated perfused rat liver, TUDCA (25 microM) stimulated a sustained increase in the biliary excretion of horseradish peroxidase, a marker of the vesicular pathway, in the presence of high, but not low extracellular Ca++ or in the cholestatic liver. In contrast, TUDCA stimulated bile flow to the same extent regardless of the concentration of extracellular Ca++ or the presence of cholestasis. In indo-1-loaded hepatocytes, basal cytosolic free Ca++ ([Ca++]i) levels were not different between normal and cholestatic cells. However, in cholestatic cells [Ca++]i increases induced by TUDCA (10 microM) and its 7 alpha-OH epimer taurochenodeoxycholic acid (50 microM) were reduced to 22% and 26%, respectively, compared to normal cells. The impairment of TUDCA-induced [Ca++]i increase in cholestatic cells could be mimicked by exposing normal cells to low extracellular Ca++ (21%) or to the Ca++ channel blocker NiCl2 (23%). These data indicate that (a) dihydroxy bile acid-induced Ca++ entry may be of functional importance in the regulation of hepatocellular vesicular exocytosis, and (b) this Ca++ entry mechanism across the plasma membrane is impaired in cholestatic hepatocytes. We speculate that the beneficial effect of ursodeoxycholic acid in cholestatic liver diseases may be related to the Ca+(+)-dependent stimulation of vesicular exocytosis by its conjugate.

Acetylglucosaminidase↗

PubMed2003

Role of PGE2 on gallbladder muscle cytoprotection of guinea pigs.

H2O2 and taurochenodeoxycholic acid (TCDC) impair the contraction induced by CCK-8, ACh, and KCl without affecting the actions of PGE2 and damage functions of membrane proteins except for PGE2 receptors. The aim of this study was to examine whether the preserved PGE2 actions contribute to cytoprotective mechanisms against reactive oxygen species. Muscle cells from guinea pig gallbladder were obtained by enzymatic digestion. Levels of lipid peroxidation and activities of SOD and catalase were determined by spectrophotometry. Pretreatment with PGE2 prevented the inhibition of H2O2 or TCDC on agonist (CCK-8, ACh, and KCl)-induced contraction and reduced the expected increase in lipid peroxidation and activities of catalase and SOD caused by H2O2 and TCDC. Incubation with CCK-8 for 60 min desensitized CCK-1 receptors up to 30 min, whereas no receptor desensitization was observed after PGE2 pretreatment. Cholesterol-rich liposome treatment enhanced the inhibition of H2O2 and TCDC on agonists-induced contraction, including that of PGE2. Pretreatment with PGE2 before H2O2 and TCDC did not completely block their inhibition on agonist-induced contraction. Cholesterol-rich liposome treatment impaired the expected increase in catalase activities in response to PGE2. We conclude that pretreatment with PGE2 prevents the muscle cell damage caused by H2O2 and TCDC due to the resistance of PGE2 receptors to agonist-induced desensitization. The preservation of PGE2 receptors may be designed to conserve these cytoprotective functions that are, however, impaired by the presence of excess cholesterol in the plasma membrane.

Acetylcholine↗