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PubMedDate not supplied

[Changes in the content of bile acids and lipids in human bile during head-down tilt hypokinesia and their correction].

The spectrum of bile acids and bile lipids in men exposed to 120-day head-down tilt was investigated. The test subjects were subdivided in to four groups: group 1-bed rest per se, group 2-bed rest + exercise, group 3-bed rest + drugs normalizing calcium metabolism, and group 4-bed rest + exercise + drugs. It was anticipated that biliary concrements would primarily be formed in group 1 and 2 subjects. They showed a low level of bile acids and a high content of total Ca and cholesterol in the bile, which was more pronounced in the C portion (decrease of the cholate/cholesterol coefficient). Group 2 subjects displayed a modified synthetic function of the liver: prevalence of tauroconjugates in the bile (decrease of the ratio of glucoconjugates to tauroconjugates). Group 3 and 4 subjects showed a faster synthesis of bile acids in the liver and a lower content of total calcium and cholesterol in the bile, the latter being more distinct in group 4 subjects. Positive dynamics of these parameters is a factor responsible for a reduced lithogeny of the bile. However, the test subjects of these groups exhibited hazardous changes that may be responsible for concrement formation. This is indicated by a lower concentration of the lipid complex in the bile, possibly at the expense of a lower content of phospholipids. This emphasizes the necessity of further search for prophylactic procedures aimed at normalizing the synthetic function of the liver under hypokinetic conditions.

Adult↗
PubMed1977

Bile acids in serum and bile of infants with cholestatic syndromes.

The concentration of individual bile acids in serum was measured in 18 neonates and infants with various cholestatic conditions (extrahepatic biliary atresia, neonatal hepatitis syndrome, chronic intrahepatic cholestasis and posthemolytic cholestasis). The cholate/chenodeoxycholate ratio in serum was smaller than one in all patients with neonatal hepatitis syndrome or extrahepatic biliary atresia, cholestatic conditions which were accompanied by signs of liver cell injury. It was greater than one in the patients with chronic intrahepatic cholestasis. Administration of cholestyramine to patients with patent extrahepatic bile ducts decreased the total concentration bile acids in serum and elevated the cholate/chenodeoxycholate ratio. Thus, cholestyramine administration may be of diagnostic value for evaluation of bile duct patency in cholestasis of infancy. Differences between the bile acid pattern in serum and bile were observed. Thus, the cholate/chenodeoxycholate ratio was always higher in bile than in serum. 3beta-hydroxy-5-cholenoic acid found in serum was not detectable in bile. This finding suggests that impairment of biliary excretion rather than increased hepatic synthesis is responsible for elevation of this monohydroxy bile acid in serum.

Bile↗
PubMed1983

Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid on bile acid kinetics and biliary lipid secretion in humans. Evidence for different modes of action on bile acid synthesis.

The effects of ursodeoxycholic acid on biliary lipid secretion and bile acid kinetics were determined in 12 men. For comparison, eight of the subjects were also treated with chenodeoxycholic acid using a crossover study design. The daily dose of each bile acid was 15 mg/kg body wt; each treatment period lasted for 5-6 wk. Kinetics of cholic acid and chenodeoxycholic acid, hepatic secretion rates of biliary lipids, and lipid composition of concentrated fasting duodenal bile were determined before and at the end of each treatment period. The synthesis rates of cholic acid and chenodeoxycholic acid were increased by approximately 80% and 40%, respectively, during treatment with ursodeoxycholic acid. The fractional catabolic rates of the two bile acids were increased by approximately 50%, whereas the pool sizes remained unchanged. Under similar conditions, administration of chenodeoxycholic acid reduced the pool size as well as the synthesis rate of cholic acid by approximately 70%. Ursodeoxycholic acid reduced the hepatic secretion of cholesterol to a higher extent (approximately 50%) than did chenodeoxycholic acid (approximately 30%). The secretion rates of bile acids and phospholipids remained essentially unchanged during the two treatment periods. Fasting duodenal (gallbladder) bile was unsaturated with cholesterol during both regimens. It is concluded that the two bile acids exert different effects on bile acid metabolism. The enhanced conversion of cholesterol to bile acids observed during ursodeoxycholic acid treatment may at least partly explain why ursodeoxycholic acid can reduce the biliary output of cholesterol without suppressing hepatic cholesterol synthesis.

Bile↗
PubMed1982

Post-operative bile secretion in man--quantification of bile fraction utilizing unlabelled mannitol.

Thirty-eight patients with external bile fistula created operatively for choledocholithiasis or malignant tumors were subjected to measurement of biliary mannitol clearance as an indicator of canalicular bile flow. The clearance measurement was performed by the single injection method in 29 cases and the constant infusion method in 12 cases, either of which consisted of administering mannitol intravenously and then directly measuring its concentrations in the plasma and the bile by Tibbling's method. The clearance value of either method was in good agreement with each other, and the bile fractions thus obtained were almost equal to those obtained from the clearance measurement done by Boyer, using radioisotope. The bile fractions were measured in 8 patients with T-tube on the 2nd and 16th post-operative days. Ductal bile flow was easy to vary, accelerated in cholangitis or bile duct dilatation and decreased as the infection subsided or the obstruction was relieved, while canalicular bile flow steadily increased postoperatively. However, of the patients given biliary drainage for obstructive jaundice due to malignant tumors, 4 cases with persistent postoperative hyperbilirubinemia had the reduced canalicular flow. Three other patients presenting with excessive bile output showed not only low canalicular flow but also high ductal flow.

Bile↗
PubMed1983

Bile salt-associated electrolyte secretion and the effect of sodium taurocholate on bile flow.

Sodium taurocholate has a remarkably varied effect on bile flow. Preisig et al. showed that a portion of electrolyte secretion is related to bile salt secretion, and other studies have suggested that this fraction of electrolyte secretion is important in bile salt--dependent flow. In the present study in the baboon and the dog, it was found that the magnitude of bile salt-associated electrolyte secretion was closely correlated to the effect of sodium taurocholate on bile flow. Theophylline, an agent widely used to alter cellular electrolyte transport, simultaneously reduced the fraction of biliary electrolyte secretion related to bile salts and the effect of the bile salt on flow. The study suggests an important role for electrolyte secretion in the modulation of the effect of bile salts on bile flow.

Animals↗
PubMed1982

[Diversion of bile into the distal ileum in swine: effect on bile acid secretion and digestive utilization of the diet].

Bile salt output and digestive utilization of a high-lipid diet were studied in pig bile collected from the common bile duct and infused into the duodenum then into the distal ileum of the animal. Five Large-White pigs of 50 kg body-weight were fitted with three permanent fistulae, one in the common bile duct for complete collection of bile secretion, and the other two in the duodenum and the ileum (at about 80 cm from the ileo-caecal valve) for returning the secretion to the animal. The diversion of the bile into the distal ileum led to a significant 82 p. 100 decrease in daily bile acid output and a 36 p. 100 decrease in apparent digestibility of dietary energy when compared with values obtained when bile was infused into the duodenum. The latter decrease was mainly due to a marked diminution ( - 60.4 p. 100) of the digestive utilization of the dietary lipids. The results show the role of the pig small intestine in maintaining an efficient enterohepatic circulation of bile acid as a result of optimal utilization of the dietary lipids.

Animals↗
PubMed1994

Short-term effects of simvastatin on bile acid synthesis and bile lipid secretion in human subjects.

To test whether de novo synthesis of cholesterol is a limiting factor for bile acid synthesis, we studied the acute effect of simvastatin, an inhibitor of HMG-coenzyme A reductase (the limiting step of cholesterol synthesis) on bile acid synthesis and biliary lipid secretion in subjects with interrupted enterohepatic circulation. In these conditions bile acid synthesis is derepressed and is assumed to equal biliary bile acid secretion. Five cholecystectomized patients fitted with T-tubes were studied. All subjects were administered simvastatin (80 mg as a single dose) 5 days after surgery. Bile was collected in 3-hr intervals for 15 hr before and 30 hr after the administration of the drug. During the experiment we kept the enterohepatic circulation of bile acid interrupted by inflating an occludable balloon inserted, during cholecystectomy, in the common bile duct. Simvastatin induced significant decreases of plasma total and low density lipoprotein cholesterol concentrations, from 163 +/- 29 mg/dl and 97 +/- 24 mg/dl of the pretreatment value to 144 +/- 30 mg/dl and 82 +/- 22 mg/dl 18 hr after simvastatin administration, respectively. Bile flow tended to increase after simvastatin, and the mean values from the third to the 15th hour after simvastatin administration (22.1 +/- 1.9 ml/hr) were significantly greater than the mean values of the pretreatment period (19.9 +/- 2.8 ml/hr). Concomitantly biliary bile acid, cholesterol and phospholipid concentrations fell from basal values of 15.9 +/- 5.1, 2.3 +/- 0.3 and 5.5 +/- 0.3 mmol/L to mean values, after treatment, of 9.0 +/- 3.5, 1.9 +/- 0.5 and 3.0 +/- 0.9 mmol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1976

The effect of diet on hepatic bile formation and bile acid metabolism in squirrel monkeys with and without cholesterol gallstones.

In order to explain why squirrel monkeys on some experimental diets develop cholesterol gallstones, we made a number of measurements on bile acid kinetics and on bile secretion and composition. The pool size of cholic acid was much greater in monkeys on a commercial diet than in any group on a semipurified diet. It was also greater in squirrel monkeys on a lithogenic diet but without gallstones than in monkeys from the same diet group with gallstones. The half-lives of cholic acid tended to be proportional to pool size, and absolute rates of cholic acid synthesis were, therefore, not much affected by diet. Diet did not affect the pool sizes and half-lives of chenodeoxycholic acid as much as those of cholic acid. Dietary cholesterol increased concentrations of cholesterol relative to bile acids and phospholipids in hepatic bile as well as absolute secretory rates of all three components. Interruption of the enterohepatic circulation of bile in fasted monkeys with gallstones resulted in a more rapid and marked increase in the relative cholesterol concentration and decline in the absolute concentration of bile acids in hepatic bile than occurred for monkeys without gallstones. This was due to the low proportion of the bile acid pool outside the gallbladder and the low rate of new bile acid synthesis of the monkeys with gallstones during fasting.

Animals↗
PubMedDate not supplied

Hepatic transport of sulfated and nonsulfated bile acids in the rat following relief of bile duct obstruction.

The effect of bile duct ligation for 5 days on the hepatic transport of sulfated and nonsulfated bile acids was studied. Tracer doses of radioactive bile acids [3H]taurochenodeoxycholate-3-sulfate [3H]chenodeoxycholate-3-sulfate, [3H]taurochenodeoxycholic acid and [14C]taurocholic acid were injected 90 min after relief of obstruction when the plasma total bile acid concentration had reverted to normal. Plasma clearance and biliary excretion of sulfated bile acids were lower than those of nonsulfated bile acids, particularly in the cholestatic rats (p less than 0.02). For each bile acid, hepatic transport in the cholestatic rats was significantly reduced compared with the control rats. [3H]Chenodeoxycholate-3-sulfate and [3H]taurochenodeoxycholic acid were partially metabolized to [3H]taurochenodeoxycholate-3-sulfate prior to biliary excretion. This data suggests that the hepatic transport system for sulfated bile acids is less efficient and more easily impaired by cholestasis than that for nonsulfated bile acids.

Animals↗
PubMed1998

Hepatic bile versus gallbladder bile: a comparison of protein and lipid concentration and composition in cholesterol gallstone patients.

Many studies have demonstrated that gallbladder bile (but not hepatic bile) of animals or patients with cholesterol gallstones contains higher protein concentrations than does gallbladder bile of control patients without stones or with pigment stones. The underlying defect has not been elucidated. To establish whether there is net production or net absorption/degradation of protein by gallbladder epithelium for different classes of protein, paired samples of hepatic and gallbladder bile were obtained from fourteen patients with cholesterol gallstones during elective cholecystectomy. In these paired samples, lipid and protein composition were determined. To obtain the concentration ratio (CR) of protein and lipid, its concentration in the gallbladder was divided by the concentration determined in the paired hepatic bile sample. The CR of bile salts was used as a parameter for water absorption in the gallbladder. Of the biliary proteins that were determined only mucin, albumin, immunoglobulin (Ig) G, and aminopeptidase N appeared to increase in the gallbladder from another cause than water absorption. A strong correlation was found between mucin, albumin, and IgG. Haptoglobin, alpha1-acid glycoprotein, IgM, and IgA appeared to be absorbed by gallbladder epithelium in the majority of patients. In cholesterol gallstone patients, total protein concentration in gallbladder bile of cholesterol gallstone patients is increased when compared with hepatic bile. The increase in protein concentration cannot be explained for all bile samples solely by water absorption. In this study we show that the defect is largely caused by a selective increase in albumin, mucin, and IgG. All other proteins which were investigated are taken up by the gallbladder.

Bile↗
PubMed2001

Bile acid sequestrants based on cationic dextran hydrogel microspheres. 2. Influence of the length of alkyl substituents at the amino groups of the sorbents on the sorption of bile salts.

Cationic dextran hydrogel microspheres with pendant quaternary ammonium groups having alkyl substituents (C(2)-C(12)) at quaternary nitrogen were synthesized. The in vitro sorption of sodium salts of four bile acids (glycocholic, cholic, taurocholic, and deoxycholic acids) with these hydrogels was studied as a function of substituent alkyl chain length and bile acid hydrophobicity. Sorption experiments were performed in phosphate buffer solutions (pH 7.4) containing one bile salt (individual sorption) or mixtures of several bile salts (competitive sorption). Parameters for individual sorption were calculated taking into consideration the stoichiometric and cooperative binding of bile salts to oppositely charged polymer hydrogels. The results show that the increase in the length of the alkyl chain of the substituent leads to an increase in both ionization constant K(0) and overall stability constant of binding K, but decreases the cooperativity parameter u. The competitive sorption studies indicate that the hydrogels display a good affinity for both dihydroxylic and trihydroxylic bile salts. The molar ratio of maximum amounts bound for the two types of bile acid is 2 to 1, which is much lower than those reported for other cationic polymers recommended as bile acid sequestrants. The binding constants for the sorption of bile salts by some dextran hydrogels are 20-30 times higher than those obtained for cholestyramine under similar sorption conditions.

Alkylation↗
PubMed1977

Relative concentrations of individual nonsulfated bile acids in the serum and bile of patients with cirrhosis.

The relative concentrations of individual nonsulfated bile acids were determined in samples of serum and bile obtained simultaneously from 16 patients with biopsy-proven alcoholic cirrhosis. A highly significant (P less than 0.001) correlation was found between the fasting relative concentrations of each of the three major bile acids (cholic, chenodeoxycholic, and deoxycholic) in serum and bile. This relationship persisted after manipulation of bile acid pools produced by feeding of individual bile acids. We conclude that the relative concentrations of individual nonsulfated bile acids in serum accurately reflect those in bile and that measurement of individual serum bile acids may be used for screening and serial determination purposes. In particular, low levels of biliary deoxycholate can be reliably predicted by serum measurements.

Adult↗
PubMed2000

The cytotoxic effects of bile acids in crude bile on human pancreatic cancer cell lines.

Pancreatic cancer frequently causes extrahepatic cholestasis. To identify the direct effects of bile acids in jaundiced serum on pancreatic cancer, the proliferation of PANC-1 and MIA PaCa-2 cells as well as the ultrastructural alteration of PANC-1 cells cultured in crude bile modified media were studied. The growth of these cells in the RPMI-1640 media with or without 1%, 2%, and 4% of the refined crude bile was assessed after 48 and 96 h of incubation. The ultrastructure of PANC-1 cells was investigated by scanning and transmission electron microscopy after 24 and 48 h of incubation. The proliferation of both cell lines in the bile-treated media was greatly inhibited. The inhibitory rates of bile on PANC-1 ranged from 24.1% +/- 3.3% to 66.9% +/- 6.6% (P < 0.01) and those on MIA PaCa-2 ranged from 16.7% +/- 3.8% to 50.7% +/- 5.5%. (P < 0.01). When the bile-added media were replaced, the cells were able to restore their proliferating ability. The PANC-1 cells incubated in the bile-supplied media indicated that the mirovilli, mitochondria, and other organelles had thus been injured. These results suggest that bile acids appear to inhibit the proliferation of PANC-1 and MIA PaCa-2 cells, and the probable inhibitory mechanism is mainly considered to be due to the cytotoxicity of such bile acids.

Bile Acids and Salts↗
PubMed2006

Interaction of native bile acids with human apical sodium-dependent bile acid transporter (hASBT): influence of steroidal hydroxylation pattern and C-24 conjugation.

PURPOSE: The human apical sodium-dependent bile acid transporter (hASBT) is a potential target for drug delivery, but an understanding of hASBT substrate requirements is lacking. The objective of this study was to characterize hASBT interaction with its native substrates, bile acids, and to evaluate C-24 conjugation and steroidal hydroxylation on transport affinity and inhibition potency. METHODS: Transport and inhibition kinetics of 15 bile acids were evaluated (cholate, chenodeoxycholate, deoxycholate, ursodeoxycholate, and lithocholate, including their glycine and taurine conjugates) with an hASBT-Madin-Darby canine kidney (MDCK) monolayer assay. Samples were analyzed via liquid chromatography-mass spectrometry (LC-MS) or chromatography-mass spectrometry-mass spectrometry (LC-MS-MS). RESULTS: C-24 conjugation improved the inhibitory potency of all native bile acids. There was an inverse association between number of steroidal hydroxyl groups and inhibitory potency. Glycolithocholate and taurolithocholate were the most potent inhibitors. Results from transport studies followed trends from inhibition studies. Conjugated dihydroxy and monohydroxy bile acids exhibited the highest hASBT-mediated transport (i.e., lower Kt and higher Jmax). Across the 15 bile acids, Kt generally followed Ki. Additionally, Jmax correlated with Ki, where greater inhibition potency was associated with higher transport capacity. CONCLUSION: C-24 conjugation and steroidal hydroxylation pattern modulated native bile acid interaction with hASBT, with C-24 effect dominating steroidal hydroxylation effect. Results indicate that bile acid binding to hASBT may be the rate-limiting step in the apical transport of bile acids.

Amination↗
PubMed1991

Precipitation and 13C-NMR relaxation enhancement measurements of the interactions of bile acids with synthetic cationic bile acid derivatives, and with spin labelled fatty acids.

In an investigation of novel potential bile acid sequestrants, the affinities of the sodium salts of the glycine and taurine conjugates of naturally occurring bile acids (cholate, deoxycholate, chenodeoxycholate and lithocholate) for several cationic ammonium bile acid derivatives have been investigated by measurements of the extent to which the derivatives are able to precipitate the bile acids. This is roughly proportional to the lipophilicity of the interacting species. Thus, amino and ammonium derivatives of cholic acid do not precipitate taurocholate or glycocholate to any great extent, whereas ammonium derivatives of deoxycholate and lithocholate are much more effective. To complement the precipitation measurements, high resolution 13C-NMR has been applied to investigate the weaker interactions between the ammonium cholate derivative and glycocholate, glycodeoxycholate and glycochenodeoxycholate. Addition of either of the latter two bile acids to the cationic ammonium compound results in considerable broadening of the 13C resonances of both species, indicating the formation of relatively rigid structures. In addition, we have used T2 relaxation enhancement induced by spin-labelled fatty acids to examine the mechanism of interaction with bile acids of amphiphilic anions, which might compete with bile acids for sites on bile acid sequestrants. Low concentrations of 16-DOXY L-Stearate dramatically broaden the 13C-NMR resonances of deoxycholate carbons 19, 18 and 7 in particular, while 5-DOXY L-Stearate exerts much less specific effects. These results have been incorporated into a snapshot model of bile acid-fatty acid interactions.

Bile Acids and Salts↗
PubMed1988

Effects of intestinal microbial bile salt sulfatase activity on bile salt kinetics in gnotobiotic rats.

Hepatic sulfation is thought to promote fecal excretion of lithocholate in humans by impairing the enterohepatic recirculation of the compound. Sulfatases produced by the gut flora may, at least in part, counteract this process. To investigate this interaction, female germfree rats, which are known to excrete considerable amounts of sulfated bile salts, were selectively associated with a bile salt desulfating flora. In these rats nearly all cecal, colonic, and fecal bile salt sulfate esters were hydrolyzed, resulting in a decrease of total fecal bile salt excretion of greater than 25% compared with gnotobiotic rats without a bile salt desulfating flora. Desulfation of allochenodeoxycholate, the major sulfated bile salt in germfree rats, led to an enhanced recirculation and 12 alpha-hydroxylation of the compound in the liver, resulting in an increased fecal output of allocholate. Microbial desulfation of intraperitoneally injected [24-14C]taurolithocholate-3-sulfate caused a fivefold decrease of the fecal plus urinary excretion rate of the isotope to approximately that found for unsulfated [24-14C]taurolithocholate. Coassociation of the gnotobiotic rats with a microflora that normalized the small intestinal transit time and cecal size led to a rise of total fecal bile salt excretion of greater than 30% and a twofold accelerated excretion of both sulfated and unsulfated injected [24-14C]taurolithocholate. We conclude that in rats the gut flora rapidly desulfates intestinal bile salt sulfates, enhancing the enterohepatic recirculation and subsequent hydroxylation of the desulfated bile salts. In addition, these data illustrate the importance of having a well-defined microflora to normalize intestinal transit time and cecal size of gnotobiotic animals when performing kinetic studies of enterohepatic circulating compounds.

Animals↗
PubMed1992

Effect of cholylsarcosine on hepatic cholesterol and bile acid synthesis and bile secretion in rats.

The regulatory and secretory properties of cholylsarcosine (C-sar), a synthetic conjugated bile acid analogue that resists deconjugation and dehydroxylation, were compared with those of the natural conjugates of cholic acid. After continuous intraduodenal infusion of cholylsarcosine (C-sar), cholyltaurine (C-tau), or cholylglycine (C-gly) at 36 mumol/100 g.h, the infused bile acid in each case became the predominant biliary bile acid. After 48 hours, infusion of C-sar, C-tau, and C-gly suppressed the activity of cholesterol 7 alpha-hydroxylase (C7 alpha H; rate-limiting for bile acid synthesis) by 65%, 78%, and 92%, respectively, compared with biliary fistula controls. After C-sar infusion, levels of C7 alpha H protein, messenger RNA, and transcriptional activity were depressed to the same extent as specific activity, indicating that C-sar, like C-tau, down-regulates C7 alpha H principally at the level of gene transcription. All three bile acids also suppressed activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (rate-limiting for cholesterol synthesis). Both short- and long-term, the three cholyl conjugates caused similar increases in bile flow and in biliary secretion of cholesterol and phospholipid. It is concluded that in the rat, cholyl conjugates per se can suppress cholesterol and bile acid biosynthesis without prior conversion to deoxycholate. The effects of C-sar on hepatic cholesterol and bile acid synthesis as well as on induced bile flow and biliary lipid secretion are essentially identical to those of the naturally occurring cholyl conjugates.

Animals↗
PubMed1979

Bile acid sulfates in serum bile acids determination.

Some bile acid sulfates were synthesized and characterized. The configuration of sulfate groups at C-3, C-7 and C-12 positions was confirmed by Nuclear Magnetic Resonance analysis. These sulfates were utilized in a study of their chemical behaviour in different analytical procedures currently used for serum bile acids determination. Procedures for bile acids extraction from serum with ethanol or Amberlite XAD-2 result in an important loss of the most polar sulfated bile acids. Complete separation of unsulfated from sulfated bile acids on Sephadex LH-20 is not achieved when deconjugation of the most polar bile acid sulfate is slow but does not produce artifacts. Enzymatic determination of bile acids gives positive response with some bile acid sulfates. The current procedures of serum bile acids determination are discussed in consideration of these results.

Bile Acids and Salts↗