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PubMed2006

[Bile salts induce differentiation in cultured human normal esophageal mucosal epithelial cells].

OBJECTIVE: To investigate the effects of bile salts on the proliferation and differentiation of human normal esophageal mucosal epithelial cells on cultured. METHODS: Normal human esophageal mucosa was obtained during operation. The esophageal epithelial cells were isolated, cultured, and treated with 6 different conjugated bile salts [glycocholate (GC), glycochenodeoxycholate (GCDC), glycodeoxycholate (GDC), taurochenodeoxycholate (TCDC), and taurodeoxycholate (TDC), all of the concentration of 50 micromol/L, and taurocholate (TC) of the concentration of 20 micromol/L], and their mixtures the concentration of 50 micromol/L respectively. One, three, and five days later MTT assay was applied to detect the cell proliferation. The cell cycle was assayed by flow cytometry with propidium iodide staining 1 and 3 d after treating with the bile salts. The cytokeratin 13 (CK13) in the differentiated cells and cytokeratin 14 (CK14) in the proliferating cells were detected by immunocytochemical assay. The concentration of intercellular calcium ([Ca(2+)]i) was analyzed by Laser Scanning Confocal Microscope (LSCM) in cells with TC, mixed bile salts and GC. RESULTS: The cultured esophageal epithelial cells treated by the bile salts, except those treated by GC for 1 - 3 days, became larger and shuttle-like, with the cell proliferation inhibited, the percentages of cells in G(0)-G(1) phase increased and percentages of cells in S phase decreased. The percentages of CK14 positive cells were increased, but the percentages of CK13 positive cells were decreased time-dependently in cells treated for 1 - 5 days. The most obvious effects were seen in those cells treated with TC. The percentage of CK13 positive cells reached 74% +/- 8% in those cells treated with TC for 5 days, higher significantly than the percentage in the control cell (22% +/- 7%), (P < 0.01). The [Ca(2+)]i increased significantly only several minutes after treatment of TC and mixed bile salts, however, GC failed to cause the increase of [Ca(2+)]i. CONCLUSION: GCDC, GDC, TC, TCDC, TDC and their mixture all induce differentiation of cultured human normal esophageal mucosal epithelial cells, but nor does GC. Increased [Ca(2+)]i is related to the TC-induced differentiation in those esophageal mucosal epithelial cells.

Bile Acids and Salts↗

PubMed1988

Prevention of endotoxaemia in obstructive jaundice--a comparative study of bile salts.

Systemic endotoxaemia is associated with postoperative renal dysfunction in obstructive jaundice, and can be prevented by the pre-operative administration of certain bile salts. In order to find the most effective bile salt for use in this condition, a comparison of the anti-endotoxic activities of different bile salts was performed. Bile salts were incubated in vitro with endotoxin and the resultant endotoxin level was measured with a quantitative limulus assay. The in vivo effects of different oral bile salts on the intestinal absorption of radiolabelled endotoxin from rats with obstructive jaundice were compared. The in vitro and in vivo anti-endotoxic activities of bile salts related to their known detergent activities. Deoxycholic acid and its conjugates were the most effective and should be the bile salts of choice for further clinical evaluation in obstructive jaundice in man.

Animals↗

PubMed2001

The mechanism of bile salt-induced hemolysis.

The hemolytic activities of sodium deoxycholate (DChol) and its tauro-conjugate (TDChol) and glyco-conjugate (GDChol) were analysed. 50 % hemolysis occurred in 30 min at pH 7.3, at the concentrations of these detergents equal to 0.044, 0.042 and 0.040 % respectively. These values are below their critical micellar concentrations. Based on its kinetics, this hemolysis is classified as being of permeability type. The detergents increase the permeability of erythrocyte membranes to KCl, and colloid osmotic hemolysis occurs. The minimum of hemolytic activity of the three cholates is at about pH 7.5. A very high increase in hemolytic activity occurs at pHs below 6.8, 6.5 and 6.2 for DChol, TDChol, and GDChol, respectively. These values are close to the pK(a) for DChol (6.2), but much higher than the pK(a) for TDChol (1.9) and GDChol (4.8). It is therefore suggested that the increase in hemolytic activity is not a result of the protonation of the anionic groups of the cholates. At acidification below pH 6, the kinetics of DChol induced hemolysis change to the damage type characterised by nonselective membrane permeability. Such a transition is not observed in TDChol and GDChol induced hemolysis. It is therefore suggested that the change in the type of hemolysis depends on protonation of the anionic group of cholates.

Bile Acids and Salts↗

PubMed1985

Hyodeoxycholic acid: a new approach to gallstone prevention.

Hyodeoxycholic acid and its isomer, 6 beta-hyodeoxycholic acid, when added to a lithogenic diet prevented the formation of cholesterol gallstones and crystals in prairie dogs. This beneficial effect occurred in the presence of bile supersaturated with cholesterol. Hyodeoxycholic acid abolished the feedback inhibition of hepatic hydroxymethylglutaryl coenzyme A reductase activity, the rate-limiting enzyme of cholesterol synthesis, and prevented elevations in serum and liver cholesterol observed in animals fed a 0.4 percent cholesterol diet. The gallbladder bile of the animals fed hyodeoxycholic acid and 6 beta-hyodeoxycholic acid contained abundant liquid crystals. This suggests that these bile acids prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones.

Animals↗

PubMed1997

Co-mutagenicity of glyco- and tauro-deoxycholic acids in the Ames test.

Mutagenicity and co-mutagenicity of glyco- and tauro-deoxycholic acids (GDCA and TDCA), which are abundant in human bile, were examined by the Ames test. The two chemicals were not mutagenic for themselves to Salmonella typhimurium TA98 and TA100, with and without S9 mix. They enhanced, however, the mutagenic activities of the pro-mutagens, 2-aminoanthracene (2AA) and benzo[a]pyrene (BaP), for both TA98 and TA100 with S9 mix. They were more co-mutagenic for the pro-mutagens on TA98 than on TA100. On TA98, the mutagenic activities of 2AA with GDCA (5 mumol/plate) and with TDCA (5 mumol/plate) were 9.7-fold and 11.8-fold as high as that of the corresponding control (2AA only), respectively. BaP with GDCA (2.5 mumol/plate) and with TDCA (2.5 mumol/plate) showed 2.8-fold and 3.0-fold increases over the corresponding control level (BaP only), respectively. It is hence concluded that GDCA and TDCA may enhance the activity of some mutagens existing in bile.

Animals↗

PubMed1985

Differential binding of glycine- and taurine-conjugated bile acids to insoluble calcium phosphate.

It is demonstrated that bile acids bind to insoluble calcium phosphate at pH values beyond 5.5. Significant binding occurs with glycine-conjugated dihydroxy bile acids. Results indicate that these bile acids are bound in a micellar mode. Taurine conjugation almost completely inhibits the binding of these bile acids to insoluble calcium phosphate. Since glycine-conjugated dihydroxy bile acids are predominant in the rabbit, but not in the rat, our results suggest an explanation for the intriguing species-dependence of casein-induced hypercholesterolaemia, which is high in the rabbit but absent in the rat.

Bile Acids and Salts↗

PubMed1979

Membranes and bile formation. Composition of several mammalian biles and their membrane-damaging properties.

The total content and profile of bile salts and phospholipids are reported for several mammalian biles. Rabbit and guinea-pig biles are characterized by high proportions of conjugated dihydroxy bile salts with respect to trihydroxy bile salts, but contain relatively little phospholipid. Both rabbit and guinea-pig biles exhibit little evidence of hepatic cell damage, even though they are able to cause membrane damage (as evidenced by lysis of human erythrocytes) at low (2--3 mM) concentrations of bile salts; this lytic behaviour is also a property of their predominant bile salts. Addition of phosphatidylcholine to the bile or bile salt is able to decrease the lytic behaviour. Perhaps the most significant observation is that these biles, and their predominant bile salts, are dramatically less lytic towards sheep erythrocytes, indicating that some factor(s) in membrane composition and structure may partly explain the resistance of membranes of the biliary tract to the presence of high concentrations of potentially membrane-damaging bile salts.

Animals↗

PubMed1996

Effects of submicellar bile salt concentrations on biological membrane permeability to low molecular weight non-ionic solutes.

Bile salts have been hypothesized to mediate cytotoxicity by increasing membrane permeability to aqueous solutes. We examined whether submicellar bile salt concentrations affect model and native membrane permeability to small uncharged molecules such as water, urea, and ammonia. Osmotic water permeability (Pf) and urea permeability were measured in large unilamellar vesicles composed with egg yolk phosphatidylcholine (EYPC) +/- cholesterol (Ch) or rat liver microsomal membranes by monitoring self-quenching of entrapped carboxyfluorescein (CF). Ammonia permeability was determined utilizing the pH dependence of CF fluorescence. Submicellar bile salt concentrations did not significantly alter Pf of EYPC +/- Ch or rat liver microsomal membranes. At taurodeoxycholate (TDC) or tauroursodeoxycholate concentrations approaching those that solubilized membrane lipids, CF leakage occurred from vesicles, but Pf remained unchanged. Higher bile salt concentrations (0.5-2 mM TDC) did not alter Pf of equimolar EYPC/Ch membranes. The activation energy for transmembrane water flux was unchanged (12.1 +/- 1.2 kcal/mol for EYPC) despite the presence of bile salts in one or both membrane hemileaflets, suggesting strongly that bile salts do not form transmembrane pores that facilitate water flux. Furthermore, submicellar bile salt concentrations did not increase membrane permeability to urea or ammonia. We conclude that at submicellar concentrations, bile salts do not form nonselective convective channels that facilitate transmembrane transport of small uncharged molecules. These results suggest that bile salt-mediated transport of specific substrates, rather than nonselective enhancement of membrane permeability, underlies bile salt cytotoxicity for enterocytes and hepatocytes.

Ammonia↗

PubMed1981

Bile acid inhibition of vitamin B12 binding by intrinsic factor in vitro.

The effect of conjugated and unconjugated bile acids on the binding of vitamin B12 to intrinsic factor was investigated. The dihydroxy bile acids (deoxycholic, glycodeoxycholic, taurodeoxycholic, glycochenodeoxycholic, and taurochenodeoxycholic) inhibit the binding of intrinsic factor to vitamin B12 at physiological concentrations. On the other hand, the trihydroxy bile acids (cholic, glycocholic, and taurocholic) are not effective in this respect. The inhibition is dependent both on concentration and time, and its pattern is similar to that previously reported for duodenal juice. On column chromatography, there is a close correlation between the degree in intrinsic factor inhibition and the total acid concentration in the duodenal juice. The binding of vitamin B12 by R protein in saliva is not affected by bile acids. The results show that bile acids at concentrations found in duodenal juice inhibit intrinsic factor vitamin B12 binding. It is suggested that this observation may have physiological significance for vitamin B12 absorption.

Bile Acids and Salts↗

PubMed1993

Different resistance of mammalian red blood cells to hemolysis by bile salts.

To evaluate why hemolysis of red blood cells (RBC) by bile acids varies in different mammalian species, we determined the mean corpuscular volume (MCV), lipid content and the concentrations of the conjugates of deoxycholate and of NaCl inducing 50% hemolysis of RBC from healthy humans, pigs, horses, cows, sheep and jaundiced humans. A volume of 0.05 mL of washed RBC at 1% hematocrit, which has the same lipid content but different phospholipid composition and number of erythrocytes (owing to the variable MCV), was incubated in taurodeoxycholate (TDC) solution (0-5 mM) to determine the TDC concentration inducing 50% hemolysis (TDC50). The TDC50 was highest in RBC of sheep and decreased within the series sheep > pig > cow > horse > healthy human > jaundiced human, which have generally increasing MCV. The osmotic resistance followed an inverse order, with jaundiced human > healthy human > horse > cow > pig > sheep. Although we found no correlation between the TDC50 and phospholipid composition of the erythrocytes tested, the extent of bile salt-induced hemolysis seemed to depend on both the MCV and the number of erythrocytes in the incubation medium.

Animals↗

PubMed2000

Interactions between food components and drugs. Part 8: Effect of pectins and bile acid preparations forming stable mixed micelles on transport of quinine in vitro.

Interactions between quinine and acetylated pectin, amidated pectin and pectin with blockwise arrangement of the free carboxyl groups as well as interactions between quinine and bile salt preparations forming stable mixed bicelles have been investigated. A diffusion cell with two compartments and an artificial lipid membrane and a filter-grown colon carcinoma cell line (Caco-2) have been used. Depending on structural parameters, pectin preparations diminished the rate of permeation of the drug. Above the critical micelle concentration, the bile salt preparations influence the quinine transport stronger than the pectin preparations. The strongest inhibition of the quinine permeation showed a stable mixed micelle preparation consisting of glycodeoxycholate, palmitic acid and lecithin. The Caco-2 cell line appears to be not as suitable as artificial lipid membranes to study drug transport in the presence of the bile salt preparations.

Antimalarials↗

PubMed1994

Role of plasma membrane ganglioside sialidase of human neuroblastoma cells in growth control and differentiation.

In cultured human neuroblastoma cells (SK-N-MC), a plasma membrane-bound besides a lysosomal ganglioside GM3 sialidase was detected. Both activities can be distinguished by the specific activation with detergents, as well as differential inhibition by Cu++. Plasma membrane and lysosomal sialidase specific activities showed strikingly different behaviour during the growth phase of neuroblastoma cells. Thus, the plasma membrane sialidase increased about 15-fold and mirrored cell growth, it differed from the kinetics of ornithine decarboxylase, an early marker of cell proliferation. The lysosomal sialidase, on the other hand, exhibited constant specific activities during growth of the cells, as did lysosomal and plasma membrane marker enzymes. When the sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid was included in the culture medium, a profound change in proliferation kinetics was observed, indicating a release from density-dependent control of cell division. Additionally, the inhibitor abolished the increase of the biochemical differentiation marker acetylcholinesterase. The results suggest an important role of the ganglioside sialidase of the plasma membrane in the processes of proliferation control and differentiation in this neuronal cell system.

Acetylcholinesterase↗

PubMed1997

[Pre- and post-operative changes in serum levels of glycocholic acid and 3,5,3'-triiodothyronine and their clinical significance in patients with cholelithiasis].

Pre- and post-operative changes of serum glycine-conjugated cholic acid (CG) and 3,5,3'-triiodothyronine (T3) levels were observed in twenty-two patients with cholelithiasis. The increase of the levels of serum CG varied with the patients; the highest levels were seen in patients with cirrhosis. After operation, the levels of serum CG and T3 were decreased significantly in patients without cirrhosis. There was positive correlation between serum CG and T3 (r = 0.4667, P < 0.01). It is indicated that the lowering of serum CG after operation may be related to the lowering of serum T3; the significant increase of serum CG level is useful to the diagnosis of liver cirrhosis, which is more sensitive than Type B ultrasonography or routine examination of liver function.

Adult↗

PubMed1987

Intraduct enterokinase is lethal in rats with experimental bile-salt pancreatitis.

Controlled intraduct infusion and peri-acinar dispersal of 100 microliter buffer containing sodium glycodeoxycholate (GDOC) at concentrations of 8.5, 17 and 34 mmol/l in rats caused a progressively severe acute pancreatitis from which none of the animals died over the experimental period. Infusion of affinity-purified active human enterokinase in buffer did not cause pancreatitis, presumably because of the inability of the macromolecule to gain access to its specific intracellular substrate trypsinogens. The addition of enterokinase 200 ng to GDOC 34 mmol/l in the infusate resulted in a severe systemic disturbance and a form of acute necrotizing pancreatitis which was uniformly and rapidly lethal. This effect was not seen when equimolar trypsin was substituted for enterokinase. These findings show that enterokinase specifically increases the lethality of experimental bile salt pancreatitis and suggest that this bile-borne enzyme may in some cases pose a significant clinical threat.

Acute Disease↗

PubMed1992

Histopathologic correlates of serum amylase activity in acute experimental pancreatitis.

The association of serum amylase activity with the extent of pancreatic injury in acute pancreatitis is unclear. To clarify this relationship, we induced acute pancreatitis ranging from mild to lethal in 118 Sprague-Dawley rats (350-450 g). This was achieved by controlled intraductal infusion of low- or high-dose bile salt, with or without enterokinase, followed by intravenous cerulein or saline for 6 hr. Serum amylase was measured at baseline and 6 hr. Pancreatic histopathology was evaluated by two blinded pathologists employing total surface scoring (N = 118) and morphometric 20-field documentation (N = 22). Serum amylase correlated best with edema (r = 0.61) and fat necrosis (r = 0.58), less well with acinar necrosis (r = 0.53) and inflammation (r = 0.50), and poorly with hemorrhage (r = 0.33) and perivascular infiltrate (r = 0.31). Inasmuch as edema and fat necrosis are not important determinants of severity, these observations could explain the poor prognostic value of serum amylase activity in patients with acute pancreatitis.

Acute Disease↗

PubMed1987

Ionic flux and mucosal ultrastructure in the rat bile-pancreatic duct. Effect of bile salt perfusion on duct integrity.

The property of the pancreatic ductal system that restricts free ionic diffusion has been termed the "pancreatic duct mucosal barrier," damage to which may be important in the pathogenesis of acute gallstone pancreatitis. The bile-pancreatic duct of the rat (BPD) was perfused in situ with a standard ionic solution. The normal duct was permeable to both chloride and bicarbonate ions, and flux (JCl-, JHCO3-) appeared to occur by passive ionic diffusion. Measurement of absolute ionic flux and transductal potential difference (PD) gave control values of JCl-, +0.92 +/- 0.15 mumol/cm/hr; JHCO3-, -1.71 +/- 0.12 mumol/cm/hr; PD -2.3 +/- 0.20 mV. The preparation was stable over the experimental period, and the results obtained were reproducible between animals. Glycodeoxycholate compromised the integrity of the BPD with an increase in ionic flux and a reduction in PD with corresponding alterations in mucosal ultrastructure. Increasing concentrations of bile salt produced more severe damage to the BPD. The BPD of the rat is therefore analogous to the pancreatic duct of the cat in possessing a mucosal barrier, and the barrier is damaged by bile salts. This preparation may be useful for studying pancreatic duct integrity, a concept of importance in the pathogenesis of acute gallstone pancreatitis.

Animals↗

PubMed1994

Pancreatic duct mucosa following bile salt injury in cats. Morphology, barrier function to pancreatic exocrine proteins and vulnerability by activated pancreatic juice.

We studied pancreatic duct mucosal morphology and barrier function to both activated and nonactivated pancreatic exocrine proteins following bile salt injury in cats. Prograde pancreatic duct perfusion with 15 mM glycodeoxycholate caused epithelial disruption with focal epithelial loss in the majority of animals. In these cats, flow of preanalyzed nonactivated rat pancreatic juice along the duct resulted in a selective loss of zymogens from the duct lumen as determined by two-dimensional isoelectric focusing-sodium dodecyl sulfate gel electrophoresis and reversed-phase high-performance liquid chromatography. Proteins lost had a low isoelectric point (< or = 5.7) and a molecular weight as large as 47,000 Da and included chymotrypsinogen 1, trypsinogens 1 and 2, and procarboxypeptidases B. Proteins with a high isoelectric point (> 5.7), a high molecular weight (> 47,000 Da), or both, were completely recovered from the duct lumen. Flow of activated rat pancreatic juice along a pancreatic duct with bile salt-induced epithelial disruptions caused additional morphologic alterations including an increase in epithelial destruction and occasional necrosis of the duct interstitial and vascular tissue. In some cats, in which the integrity of the ductal epithelium remained preserved following exposure to the bile salt, neither loss of rat pancreatic exocrine zymogens from the duct lumen nor degradation of the duct mucosa by activated rat pancreatic juice was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Effect of microcirculatory perfusion on distribution of trypsinogen activation peptides in acute experimental pancreatitis.

Extraintestinal trypsinogen activation peptides (TAP) have been shown to correlate with severity of acute pancreatitis in humans as well as in various animal models. Ischemia superimposed on experimental pancreatitis, however, increases acinar cell injury without increasing TAP in plasma. We speculated that TAP generated in the pancreas might not reach the circulation in necrotizing pancreatitis due to decreased pancreatic perfusion. To test the hypothesis that generation of TAP in plasma is related to pancreatic perfusion and that plasma TAP may therefore underestimate acinar cell injury in necrotizing disease, we correlated TAP in pancreatic tissue and body fluids with capillary pancreatic blood flow in necrotizing and edematous pancreatitis. The ratio between necrosis and TAP in tissue was similar in both models; the ratio between TAP in plasma and tissue, however, was significantly lower in necrotizing pancreatitis, indicating that a certain amount of TAP generated in the pancreas did not reach the circulation. Decreased pancreatic perfusion found in necrotizing pancreatitis was consistent with this finding. Our data suggest that TAP in tissue is most reliable to indicate severity of acute pancreatitis, whereas plasma TAP may underestimate pancreatic injury in necrotizing disease due to decreased pancreatic perfusion.

Acute Disease↗