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At least 19 recordsLinked to original sources
PubMed1976

Role of membranes in bile formation. Comparison of the composition of bile and a liver bile-canalicular plasma-membrane subfraction.

1. Enzymes, proteins, glycoproteins and lipids of rodent bile were compared with those of a plasma-membrane subfraction originating from the hepatocyte bile-canalicular membrane. 2. Three bile-canalicular glycoprotein enzyme activities were detected in bile. Comparison of the pH optimum and immunoinhibition properties of membrane and bile 5'-nucleotidase activity indicated that they were the same enzyme. Correspondence between membrane and bile alkaline phosphodiesterases also suggested that they were the same enzymes. Activities of Mg2+-stimulated adenosine triphosphatase, a lipid-dependent intrinsic membrane protein, and galactosyltransferase, a Golgi membrane marker, were not detected in bile. 3. Rodent bile contained 15 polypeptide bands that differed radically from those of bile-canalicular membranes. Bands that may correspond in molecular weight to liver plasma-membrane glycoproteins were present at low staining intensities in bile. A major protein of apparent molecular weight 49 500 was present, and albumin was detected by immunodiffusion. 4. The lipid composition of bile and bile-canalicular membrane also differed. Phosphatidylcholine accounted for 82% of rat bile phospholipids, and only trace amounts of phosphatidylinositol, phosphatidylserine and sphingomyelin were present. 5. The results indicate that in healthy animals, the bile-canalicular membrane is refractory to the action of bile acids during the secretory process. The presence of only small amounts of bile-canalicular membrane components, especially glycoprotein enzymes located at the outer face of the membrane, suggests that these are released from the membrane by bile acids after secretion of bile into the canalicular spaces.

Adenosine Triphosphatases↗
PubMed1976

The effect of thyroid hormone on bile salt-independent bile flow and Na+, K+ -ATPase activity in liver plasma membranes enriched in bile canaliculi.

The relationship between bile salt-independent canalicular flow and ATPase activity in liver plasma membranes (LPM) enriched in bile canaliculi, was studied in control, hyperthyroid, and hypothyroid rats. Canalicular bile production was significantly increased in hyperthyroid rats (3.19 +/- 0.23 mul/min per g liver) compared to controls (2.27 +/- 0.24 mul/min per g liver), while it diminished in hypothyroid animals (1.58 +/- 0.17 mul/min per g liver). Although bile salt excretion was also increased in hyperthyroid animals (62.4 +/- 13.3 vs. 41.2 +/- 8.4 nmol/min per g liver), the stimulation in canalicular secretion was primarily related to enhancement of the bile salt-independent fraction of flow (2.47 mul/min per g liver in hyperthyroid rats vs. 1.67 mul/min per g liver in controls). LPM Na+, K+-ATPase activity doubled in hyperthyroid animals (21.5 +/- 5.8 vs. 10.7 +/- 3.1 mumol Pi/mg protein per h) while Mg++-ATPase activity remained unchanged and 5'-nucleotidase activity increased to a small but significant extent. In hypothyroid rats, bile salt excretion remained unchanged from control values so that the reduced secretion was entirely secondary to an inhibition of bile salt-independent secretion (1.19 mul/min per g liver). Na+, K+-ATPase activity in the LPMs from hypothyroid animals decreased by nearly 50% (5.4 +/- 1.6 mumol Pi/mg protein per h), although comparable reductions in the specific activity of Mg++-ATPase and 5'-nucleotidase were also observed. Administration of L-thyroxine to hypothyroid animals restored both bile salt-independent canalicular secretion and membrane enzymes to control values within 2 and 4 days, respectively. Sodium dodecyl sulfate gel electrophoresis demonstrated no significant changes in LPM protein fractions from any of the treatment groups. These studies indicate that thyroid hormone has a parallel effect on bile salt-independent canalicular secretion and LPM Na+, K+-ATPase activity, supporting the hypothesis that Na+ transport and Na+, K+-ATPase may be determinants of bile salt-independent canalicular flow.

Adenosine Triphosphatases↗
PubMed1978

The extracorporeal bile duct: a new model for determination of bile flow and bile composition in the intact rat.

A new model is described which allows measurement of bile flow and sampling of bile in the intact rat with a physiologically functioning sphincter of Oddi. A number of metabolic parameters have been followed to show that animals with such an "extracorporeal bile duct" (EBD) behave as intact controls. Especially, there was no difference in the increase in body weight or hepatic fatty acid and cholesterol synthesis between EBD animals and intact controls. The amount of bile salts circulating through the biliary tract amounted to 30.5+/-1.5mumol . 100 g body wt-1 . hr-1, when diurnal variations were averaged. Animals adapted to a restricted feeding regimen showed a significant increase of bile flow and of biliary bile salt and cholesterol excretion during feeding (10AM-3 PM); these parameters reached their maximum 3 hours after onset of food intake.

Animals↗
PubMed1979

Sodium taurocholate modifies the bile acid-independent fraction of canalicular bile flow in the rhesus monkey.

Bile acid-independent secretion and the choleretic response to taurocholate were determined in rhesus monkeys fitted with indwelling silastic cannulas in the common bile ducts. Bile acids were infused intravenously in random order at 3.5, 7.0, or 10.5 mumol/min for 1.5 h each. When data were analyzed with a single regression line, bile flow increased in proportion to the level of bile acid secretion, although the y-intercepts (the conventional measurement of bile acid-independent secretion) varied widely (77.9+/-40.9 ml/24 h). The variation in y-intercepts was observed between animals and with repeated studies in the same animal and could not be explained by sex differences or the effects of the indwelling silastic cannulas, but seemed to be related to the order of bile acid infusion. With only two taurocholic acid infusion rates (7.0 and 3.5 mumol/min), [(14)C]erythritol clearance was greater per mole of secreted bile acid when the initial bile acid infusion was at the high level, but approached zero at low bile acid secretion rates, which suggests that so-called bile acid-independent canalicular flow is closely related to bile acid secretion or is small in size. The augmentation in [(14)C]erythritol clearance when the high infusion rate was given first was also associated with an increase in biliary clearance of [(3)H]inulin, which indicates that the premeability to inulin was also enhanced. Identical experiments which substituted equimolar infusions of a nonmicelle-forming bile acid (taurodehydrocholate) for taurocholate failed to demonstrate any difference in choleretic response or biliary clearance of [(3)H]inulin with the order of bile acid infusion. These experiments demonstrate that a micelleforming bile acid, taurocholate, can increase the permeability of the biliary system to large molecular weight solutes and simultaneously modify the y-intercept and the volume of bile secreted in response to the transported bile acid. Taurocholate may, therefore, modify its own choleretic response, perhaps by altering the structure or function of bile secretory membranes, and appears to be a major determinant of so-called bile acid-independent flow in rhesus monkeys.

Animals↗
PubMed1979

Effects of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the rhesus monkey: a model for chlorpromazine-induced cholestasis.

We studied the acute effects of intravenous infusions of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the alert female Rhesus monkey prepared with a total biliary fistula and in a steady bile salt secretory state. In twelve studies (three animals), five doses of radiolabelled chlorpromazine hydrochloride (1-10 mg identical to 2.8-28 mumol/kg) were infused intravenously for 1 h in random order. Cholestasis was induced within minutes in all experiments. The radiolabel appeared rapidly in bile, with similar recoveries in bile and urine and a 90% total cumulative output in 4 days. Both bile flow, bile salt and other biliary lipid outputs were inhibited in a dose related and reversible manner. The apparent bile salt independent bile flow was consistently abolished, and a prompt return to basal values occurred when biliary concentration of the drug and metabolities fell below 1-2 mM. When chlorpromazine hydrochloride was infused at three doses (2.5, 5.0 and 10.0 mg identical to 7-28 mumol/kg) during constant intravenous infusion of 14C sodium taurocholate (300 mumol/h), bile flow, total bile salt output and 14C taurocholate output decreased within minutes. This was accompanied by a progressive rise in the serum 14C taurocholate concentration. After 90 min the taurocholate specific activity in bile increased significantly indicating that bile salt synthesis was inhibited. Secretion of retained bile salts and reversal of inhibition of bile salt synthesis occurred with time: the course of both events was correlated with the dose of the drug. Thus, in monkeys, chlorpromazine hydrochloride induces reversible, dose related cholestasis suppression of the bile salt dependent and independent flow, inhibition of bile salt synthesis and impairment of biliary lipid secretion. We suggest that these effects are due to both bile salt-chlorpromazine interactions and the effect of the latter on canalicular and other membranes.

Animals↗
PubMed1978

Bile acid-induced increase in bile acid-independent flow and plasma membrane NaK-ATPase activity in rat liver.

Previous studies showed that in rats with obstruction of the bile ducts draining the median and left hepatic lobes, and in rats with normal bile ducts in which the bile acid pool size and secretion were augmented by 48-h intraduodenal infusion of taurocholate, bile acid flux through secreting hepatocytes was increased. Under these conditions, taurocholate transport maximum exhibited a time-dependent adaptation to increased secretory load.Unexpectedly, bile acid-independent canalicular flow in these experimental models also was found to be increased when measured at 48 h. Relative to controls, bile acid-independent flow per gram of nonobstructed liver was increased approximately threefold in selectively obstructed rats and 43% in bile acid-loaded rats with normal ducts. In rats infused with bile acids at similar rates for only 16 h, no increase was observed. Studies with [(14)C]erythritol suggested that the increased bile flow under these conditions was of canalicular origin.NaK-ATPase activity in canaliculi-enriched liver plasma membrane preparations from the nonobstructed lobes of selectively obstructed rats and from 48-h bile acid-loaded rats was increased by 47% and 52%, respectively, relative to controls, but was not increased in membranes from 16-h bile acid-loaded rats. Canalicular membrane 5'-nucleotidase and Mg ATPase also were increased. These studies show that augmented bile acid flux through secreting liver causes an adaptive increase in bile acid-"independent" flow and in the activity of canalicular membrane enzymes. The mechanism by which bile acids modulate this and previously reported aspects of bile secretion remains to be elucidated.

Adenosine Triphosphatases↗
PubMed1979

The effect of complete biliary obstruction on bile flow and bile acid excretion: postcholestatic choleresis in the rat.

Bile secretory function was studied in rats subjected to a 7-day obstructive cholestasis induced by complete common duct obstruction. Bile flow and bile acid excretion were examined during bile depletion, following the release of the biliary obstruction, and during the infusion of sodium taurocholate at submaximal and saturating rates. A highly significant increase, greater than 100%, in bile flow was evident in cholestatic rats at any bile acid excretory rate, when compared to control sham-operated rats. 14C-erythritol clearance measurements performed during bile depletion and during the infusion of taurocholate suggest that bile flow was mainly of canalicular origin in cholestatic rats. Estimated taurocholate transport maximum (mumol/min per rat) was not statistically different between cholestatic and control rats. However, significantly greater taurocholate plasma levels at Tm in cholestatic rats suggest a decreased efficiency of the bile acid transport process. In addition, the relationship between bile flow and bile acid excretion was found to be nonlinear at low bile acid excretory rates in cholestatic rats. Thus important changes in bile formation occurred in rats subjected to temporary obstructive cholestatis, which differ from those observed in other models of cholestasis that are associated to a reduction in bile flow and bile acid transport capacity.

Animals↗
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↗
PubMed1977

Effects of chronic choleretic infusions of bile acids on the membrane of the bile canaliculus. A biochemical and morphologic study.

To determine whether choleretic infusions of bile acids modified the function or structure of the membrane of the bile canaliculus, sodium taurocholate (NaTc) or dehydrocholate (DHC) was infused into male rats at a rate of 80 mumoles per hour over an 18-hour period. Bile was collected by fistula and phospholipid and cholesterol content was measured in bile, liver homogenates, and isolated liver plasma membranes (LPM) enriched in bile canaliculi. Na+, K+-ATPase, Mg2+-ATPase, 5'-nucleotidase, and alkaline phosphatase activities were also measured in LPM. NaTc infusions enhanced cholesterol and phospholipid output in the bile in association with a significant increase in phospholipid in both LPM and liver homogenate. Although DHC infusions resulted in a comparable excretion of bile acid, phospholipid and cholesterol output in bile did not increase from control values and the concentration of these lipids in LPM and liver homogenate also did not change. However, LPM Na+, K+-ATPase significantly increased after DHC infusions compared to NaTc-infused animals or controls. Neither bile acid altered the activities of Mg2+-ATPase, 5'-nucleotidase, or alkaline phosphatase. Both bile acids increased the diameter of the lumen of the bile canaliculus as assessed by scanning electron microscopy and produced irregularities and outpouchings in the canalicular membrane. Diverticuli and loss of microvilli were most prominent with DHC infusions whereas canalicular side branching and the density of microvilli, either remained unchanged or increased following NaTc infusions. Although the morphologic findings are qualitative, the results of these studies indicate that chronic choleretic infusions of NaTc and DHC have divergent effects, not only on enzyme activities in liver plasma membrane, but on phospholipid composition and 3-dimensional structure. These findings suggest that bile acids may after biliary secretion not only through their osmotic effects, but by modifying lipids and enzymes in the membrane of the bile canaliculus.

Adenosine Triphosphatases↗
PubMed1979

High performance liquid-chromatographic analysis of individual bile acids: free, glycine- and taurine-conjugated bile acids.

High performance liquid-chromatographic analyses of individual bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid), free and conjugated with glycine and taurine, are described. The analyses of free and glycine-conjugated bile acids are based on esterification of carboxyl group of bile acids with O-(p-nitrobenzyl)-N, N'-diisopropylisourea (PNBDI). Moreover, ursodeoxycholic acid, hyocholic acid, hyodeoxycholic acid and 3beta-hydroxy-5-cholenoic acid also are able to analyse by this method. These bile acids in biological sample were extracted by an Amberlite XAD-2 column, and separated by DEAE-Sepharose CL-6B into free, glycine- and taurine-conjugated bile acids. After the separation, free and glycine-conjugated bile acids were esterified with PNBDI directly. Because taurine-conjugated bile acids are unable to be esterified with PNBDI, these bile acids were hydrolyzed by NaOH in order to make free bile acids, and then they were esterified. Because the p-nitrobenzyl ester of bile acids has characteristic ultraviolet absorption, these compounds were separated to individual bile acids by high performance liquid-chromatography, and detected by an UV-detector. An analysis of individual bile acids in human bile was demonstrated.

Bile Acids and Salts↗
PubMed1979

Regulation of hepatic transport of bile salt. Effect of protein synthesis inhibition on excretion of bile salts and their binding to liver surface membrane fractions.

The overall transport of bile salts across the hepatocyte is characterized as a carrier-mediated process whose rate-limiting step is biliary secretion. Specific bile salt binding proteins have been identified in liver surface membrane fractions and were postulated to represent the initial interaction in bile salt translocation across both the sinusoidal and canalicular membranes. To test this hypothesis, cycloheximide was administered to rats to inhibit hepatic protein synthesis. 16 h after cycloheximide administration [14C]leucine incorporation into hepatic protein was inhibited by 93% at 1 h and 47% at 12 h. However, values of liver function tests were not increased, although serum albumin, serum alanine amino-transferase, and alkaline phosphatase were significantly decreased. Light and electron microscopy did not demonstrate necrosis or fat accumulation. The latter demonstrated minimal disorganization of rough endoplasmic reticulum and occasional lamellar whorls. 16 h after cycloheximide administration bile salt independent bile flow, basal bile salt excretion, and basal bile flow were unaltered, but the maximum bile salt transport capacity was reduced to 62% of control and 24 h later to 38%. Decreased bile salt transport was reversible, for it returned to control values after 48 h, when hepatic protein synthesis was also normal. Maximum bromosulfophthalein (BSP) transport, on the other hand, was reduced after 16 h to only 85% of control. Both bile salt and BPS maximum transport capacities decreased with time during inhibition of protein synthesis, apparently following first order kinetics. It was estimated that their half-lives are 20 h for bile salt transport and 55 h for BSP transport. These different turnover rates suggest that cycloheximide does not decrease active transport through generalized hepatic dysfunction or alteration of high energy sources possibly required for transport. The maximum number of [14C]cholic acid binding sites in liver surface membrane fractions was determined by an ultrafiltration assay. They were reduced to 68% of control after 16 h of cycloheximide and to 25% after 24 h. This reduction in the number of binding sites is apparently selective, for the activities of the liver surface membrane enzymes (Na+-K+)ATPase, Mg++-ATPase, and 5'-nucleotidase were not significantly changed. The associated alterations in bile salt transport and the maximum number of binding sites after cycloheximide administration suggests that these receptors may be the bile salt carriers.

Animals↗
PubMed1976

Effects of cholera enterotoxin, glucagon, and dibutyryl cyclic AMP on rat liver alkaline phosphatase, bile flow, and bile composition.

Cholera enterotoxin, 45 mug per 250 g body weight, administered intravenously to rats, caused a 6-fold rise in the activity of liver alkaline phosphatase in 12 hr. There was no change in bile volume or in the concentration or total bile content of Na+, K+, HCO3-, or Cl- for 36 hr after the administration of cholera toxin. However, bile phospholipid output fell markedly from a control level of 15.0 +/- 1.0 mumol per 6 hr to a low level of 4.0 +/- 1.2 mumol per 6 hr in the 12- to 18-hr collection, P less than 0.001. There was a similar fall in bile acid secretion, from a control value of 9.8 +/- 0.4 mumol per 6 hr to 4.1 +/- 0.9 mumol in the 12- to 18-hr period, P less than 0.01. The cholera effect was prolonged. Bile acid and phospholipid secretion rates did not return to control values until 30 to 36 hr after the administration of cholera enterotoxin. The cholera toxin-induced reductions in bile acid and phospholipid secretion into bile did not appear to be mediated by adenyl cyclase or cyclic AMP because neither glucagon, a known stimulator of liver adenyl cyclase, nor dibutyryl cyclic AMP had any effect on the secretion into bile of bile acids or phospholipid. The administration of cholera toxin was not associated with any increase in the secretion of free choline into bile. Glucagon and dibutyryl cyclic AMP, two other substances known to increase the activity of rat liver alkaline phosphatase, also had no stimulatory effect on the secretion of free choline into bile. The results do not support the hypothesis that the main function of rat liver alkaline phosphatase is to facilitate the excretion of free choline into bile.

Alkaline Phosphatase↗
PubMed1977

Effects of bile and bile acids on cultured human fibroblasts.

Impaired healing induced by leakage of bile has been postulated as one factor responsible for complications after reconstructive bile duct surgery. The cytotoxicity of human bile and its major bile acids on cultured human fibroblasts was therefore studied by evaluation of their effects on cell morphology and growth, on synthesis and secretion of 35SO4-mucopolysaccharides and on release of a lysosomal enzyme. Normal human fibroblasts derived from a standard culture strain (MRC-5) were grown to confluence and exposed to: (1) sterile human T-tube bile, (2) a mixture of bile acids resembling that of human bile, or (3) various concentrations of the glycine- and taurine conjugates of cholic, chenodeoxycholic or deoxycholic acid. Medium containing whole bile (total bile acid concentration 0.25, 0.75 or 1.6 mmol/l) exerted time and dose dependent cytotoxic effects on morphology and growth and release of lysosomal enzyme. Synthesis and secretion of 35SO4-mucopolysaccharides were markedly inhibited. The bile acid mixture exhibited the same time and dose dependent effects. The conjugates of deoxycholic acid were found to be the most toxic of the individual bile acids studied.

Bile↗
PubMed1977

Bile salt metabolism. II. Bile salts and disease.

Alterations of bile salt metabolism have been shown in numerous diseases. Liver damage results in elevated serum bile salt concentrations which may be useful as a sensitive index of hepatocellular disease. Changes in the relative proportions of the individual bile salts in serum occur with cholestasis. Urinary excretion of bile salts, largely in the form of sulphates, increases as a compensatory mechanism. Ileal disease or resection causes bile salt melabsorption. The increase in colonic bile salts produces a watery diarrhoea while the decrease in duodenal levels may cause steatorrhoea. Cholelithiasis may result from alteration in the relative proportions of cholesterol, lecithin and bile salts in bile. The mechanism apparently differs in various conditions predisposing to gallstone formation. A primary alteration of bile salt metabolism has been postulated in several other conditions. Considerable interest centres on the importance of metabolites of bile salts in the pathogenesis of colonic carcinoma. Chenodeoxycholic acid is a successful though costly treatment for selected patients with cholesterol gallstones. Bile salt binding agents, such as cholestyramine, are extremely useful especially in the control of pruritus in patients with cholestasis.

Animals↗
PubMed1975

Bile composition and bile cast formation after transplantation of the liver in man.

Transplantation of the liver in man is frequently complicated by biliary fistula and obstruction of the biliary tree by casts, which suggests that the composition of the bile may be abnormal. In part of the present study, bile composition was investigated in three recipients during the first few weeks after transplantation, when a T tube was in place. Supersaturation of bile with cholesterol was found in two patients immediately after surgery and during episodes of acute rejection, but bile was never lithogenic in the third. There was no evidence of bile stasis in the absence of acute rejection and bile viscosity was normal in all three patients throughout the study. Free bile acids and free bilirubin, which are relatively insoluble products of bacterial metabolism, were not present in the bile of any patient. However, chemical analysis of casts found at autopsy in a fourth recipient showed that the major component was free bilirubin. Escherichia coli was grown in cultures of the casts and the organisms were shown to possess glucuronidase activity, thus providing an explanation for the high bilirubin content. There was also some evidence in one case that damage to the bile duct mucosa has led to the precipitation of material upon it, and it is concluded that a number of factors, including infection, supersaturation with cholesterol, and mucosal damage, may be involved in bile case formation after transplantation of the liver.

Adult↗
PubMed1978

The measurement of bile acid-dependent and independent fractions of rat bile.

Bile flow and bile acid secretory rate in rate in rats with interruption of the enterohepatic circulation had a biphasic decay with the second slower slope less marked for bile flow. A direct relationship between both parameters was observed in these animals. by knowing the choleretic efficiency of bile acids calculated from the regression line, the total bile acid output and the volume of bile collected, the fraction of bile produced by other way than bile water carried by bile acids was estimated. This fraction was found to be about 65 percent of the total bile formed.

Animals↗
PubMed1977

The isolation and characterization of a bile ductule cell population from normal and bile-duct ligated rat livers.

The separation of bile ductule cells from Kupffer and sinusoidal endothelial cells in a suspension of non-parenchymal cells has been attempted. Bile duct ligation was performed so that a four-fold increase in the total number of non-parenchymal cells isolated from rat liver was attained and the proportions of both Kupffer and bile ductule cells were elevated. Rate zonal centrifugation, through a Ficoll gradient, partially separated the cells into two populations: (1) small cells (4-6 micrometer diameter) probably originating from the sinusoidal endothelium and (2) larger bile ductule and Kupffer cells (8-12 micrometer diameter). A more successful separation was achieved by isopycnic centrifugation through a linear metrizamide gradient. Bile duct ligation (14 days) altered the distribution of cells on the gradient and the peak containing bile ductule and Kupffer cells partially subdivided into the separate cell types. Antiserum raised against the bile ductule fraction was shown to be compatible with that raised against common bile duct tissue. gamma-glutamyl transpeptidase and leucine aminopeptidase activity were preferentially located in the rate zonal fraction containing bile ductule cells. Their specific activity increased after bile duct ligation as did that of beta-glucuronidase, which was raised in all cells.

Animals↗