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PubMed1980

Bile acid metabolism in fetal sheep; perinatal changes in the bile acid pool.

1. A chronic fetal bile fistula model was developed in sheep which allowed observations on fetal bile for periods of up to 10 days. A comparison of fetal, lamb and adult bile acids was made in bile fistula animals. 2. Bile was analysed by thin layer chromatography, gas liquid chromatography, and high pressure liquid chromatography. Fetal bile contained a much greater proportion of chenodeoxycholic acid (42.0 +/- 1. S.E. of mean 3.0% of total bile acids by high pressure liquid chromatography) than lamb bile (8.1 +/- 1.9%) or adult bile (5.4 +/- 0.6%). The corresponding figures for cholic acid were fetal: 45.8 +/- 2.9%, lamb: 89.1 +/- 2.9%, and adult: 75.2 +/- 2.6%. Deoxycholic acid, a secondary bile acid, was present in fetal bile (12.2 +/- 4.9%). In the lamb, deoxycholic acid comprised only 2.8 +/- 1.1% of total bile acids, compared with 19.3 +/- 2.9% in adult sheep. Taurine conjugates predominated in sheep bile, but this predominance was least marked in lamb bile. 3. The fetal bile acid pool (101 +/- 13 mu mole/kg) was significantly smaller than the neonatal pool (214 +/- 26 mu mole/kg, P < 0.01). This increase in pool size, together with the increased proportion of cholic acid, suggests a rapid rise in cholic acid synthesis soon after birth. 4. Bile acid synthetic rates were estimated from bile acid secretion rates at the nadir of the washout curves. The values obtained were 0.71 +/- 0.18 mu mole/kg.hour (adult), 0.47 +/- 0.16 mu mole/kg.hour (lamb), and 0.35 +/- 0.08 mu mole.hour (fetus). 5. In the fetus and in pregnant adult sheep, the normal increase in bile acid synthesis in response to depletion of the bile acid pool was much less marked. 6. In the fetus, biliary secretion of cholesterol and phospholipid ran parallel with bile acid secretion. Bile lipid composition was similar to that in the adult. 7. Fetal bile water production was higher, relative to bile acid secretion, than lamb or adult bile water secretion.

Animals↗
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↗
PubMed1984

Influence of bile acid structure on bile flow and biliary lipid secretion in the hamster.

A comprehensive study of the influence of bile acid structure on bile flow and biliary lipid secretion was carried out by infusing pure bile acids at a physiological rate into the proximal small intestine of a bile fistula hamster. Twelve individual bile acids, cholate (C), ursocholate (UC), chenodeoxycholate (CDC), and ursodeoxycholate (UDC) as their glycine (G), taurine (T), or unconjugated form, were studied so that influence of the hydroxy substituents as well as side-chain structure could be defined. The pattern of bile acid output was dependent on bile acid structure and reflected the site and rate of intestinal absorption. Conjugated bile acid output was delayed because of late ileal absorption, and TUC was poorly absorbed. Unconjugated trihydroxy bile acids, C and UC, also exhibited a delay in absorption, while CDC and UDC were absorbed immediately and achieved the highest bile acid output. Unconjugated bile acids were conjugated initially mostly with taurine and then mostly with glycine. The effect of glycine conjugates of each bile acid on bile flow and biliary lipid secretion was similar to that of their corresponding taurine conjugates. All conjugated bile acids induced a similar rate of bile flow (9-15 microliter bile/mumol bile acid), but unconjugated bile acids other than C induced more flow (20-25 microliter bile/mumol bile acid) than their corresponding conjugates. Conjugates of the dihydroxy bile acids induced a greater secretion of phospholipid and cholesterol than cholyl conjugates, whereas conjugates of UC were unique in inducing extremely low phospholipid and cholesterol secretion. For an increase of 1 mumol X min-1 X kg-1 in bile acid output, the increase in phospholipid secretion was 0.072 mumol X min X kg for GCDC and TCDC; 0.051 mumol X min-1 X kg-1 for GUDC and TUDC; and 0.030 mumol X min-1 X kg-1 for GC and TC. Increase in cholesterol output per mumol X min-1 X kg-1 of bile acid output was 0.013 mumol X min-1 X kg-1 for GCDC and TCDC, 0.011 mumol X min-1 X kg-1 for GUDC and TUDC, and 0.005 mumol X min-1 X kg-1 for GC and TC. In general, unconjugated bile acids induced more phospholipid and cholesterol than their corresponding conjugates; however, the rank-order effect of the steroid nucleus substituents was similar to that observed for the respective conjugates. These results indicate that both nuclear and side-chain structure influence the enterohepatic circulation and biliary secretory properties of bile acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Effect of complete sulfation of bile acids on bile formation in rats.

The effect of sulfation of common bile acids on the formation of bile was investigated in male rats by infusing them with the sulfate esters of cholic, chenodeoxycholic, deoxycholic, lithocholic or dehydrocholic acid in four step-wise, increasing doses. Each dose was infused for 30 min and bile collected every 10 min. Control studies were performed by using either albumin solution (the bile acid carrier) or corresponding nonsulfated bile acids at concentrations similar to those of the sulfated products. The secretion of sulfated bile acids was slower and less than that of nonsulfated bile acids, demonstrating transport maximum kinetics rather than the secretory rate maximum characteristic of nonsulfated bile acids. Sulfation significantly increased bile salt-independent bile flow and the choleretic potency of the bile acids tested. With the exception of deoxycholic acid, which had a slight stimulatory effect, bile acid sulfation generally prevented a rise in bile acid-dependent phospholipid and cholesterol secretion. In fact, it reduced biliary phospholipid and cholesterol secretion associated with the secretion of endogenous bile acids. These data are in agreement with the physicochemical properties of sulfated bile acids. They indicate that sulfation prevents the cholestatic action of nonsulfated bile acids, perhaps by increasing bile flow via a high choleretic potential and/or by stimulating bile acid-independent bile flow. The effect of sulfated bile acids on the secretion of biliary phospholipids may protect the canalicular membrane from the detergent properties of bile acids and may thus block the cholestasis which results from high, nonsulfated bile acid concentrations.

Animals↗
PubMed1972

Fetal bile salt metabolism. II. Hepatic excretion of endogenous bile salt and of a taurocholate load.

Bile salt metabolism was studied in fetal dogs 1 wk before term. The size and distribution of the fetal bile salt pool were measured, and individual bile salts were identified. The hepatic excretion of endogenous bile salts was studied in bile fistula fetuses, and the capacity of this excretory mechanism was investigated by the i.v. infusion of a load of sodium taurocholate-(14)C up to 20 times the endogenous pool size. The total fetal bile salt pool was 30.9+/-2.7 mumoles, of which two-thirds was in the fetal gallbladder. Expressed on a body weight basis, this was equal to approximately one-half the estimated pool size in the adult dog (119.2+/-11.3 vs. 247.5+/-33.1 mumoles/kg body wt). Measurable quantities of bile salt were found in small bowel (6.0+/-1.8 mumoles), large bowel (1.1+/-0.3 mumoles), liver (1.2+/-0.5 mumoles), and plasma (0.1+/-0.03 mumoles). Plasma bile salt levels were significantly greater in fetal than in maternal plasma (1.01+/-0.24 mug/ml vs. 0.36+/-0.06 mug/ml; P < 0.05). Fetal hepatic bile salt excretion showed a fall over the period of study from 2.04+/-0.34 to 0.30+/-0.07 mumoles/hr. The maximal endogenous bile salt concentration in fetal hepatic bile was 18.7+/-1.5 mumoles/ml. The concentration in fetal gallbladder bile was 73.9+/-8.6 mumoles/ml; and, in those studies in which hepatic and gallbladder bile could be compared directly, the gallbladder appeared to concentrate bile four- to fivefold.Taurocholate, taurochenodeoxycholate, and taurodeoxycholate were present in fetal bile, but no free bile salts were identified. The presence of deoxycholate was confirmed by thin-layer chromatography and gas liquid chromatography, and the absence of microorganisms in fetal gut suggests that it was probably transferred from the maternal circulation. After infusion of a taurocholate load, fetal hepatic bile salt excretion increased 30-fold, so that 85-95% of the dose was excreted by the fetal liver during the period of observation. Placental transfer accounted for less than 5% of the dose. Fetal bile volume increased 15-fold on average, while bile salt concentrations increased two- to threefold. It is concluded that bile salt is taken up, conjugated, and excreted by the fetal liver with remarkable efficiency. The excreted material is either stored and concentrated in the fetal gallbladder or released into the intestine and reabsorbed to be reexcreted in bile.

Animals↗
PubMed1975

The intermicellar bile salt concentration in equilibrium with the mixed-micelles of human bile.

The intermicellar bile salt concentration in equilibrium with the bile salt-lecithin-cholesterol mixed-micelle has been studied in human bile. Equilibrium-dialysis, used to measure the biliary intermicellar bile salt concentration, has been validated as an applicable method by studying the cholate-lecithin mixed-micelle, for which intermicellar bile salt concentration values have previously been reported. The intermicellar bile salt concentration of bile was essentially independent of ionic strength in the range 0.05-0.15 M chloride. Simple dilution of bile lowered the intermicellar bile salt concentration (about 2/3 reduction for each two-fold dilution). This reduction occurred because of a simultaneous decrease in the molar ration of bile salt/phospholipid in the micelle. Dilution of micelles with micellar bile salt/phospholipid held constant did not affect the intermicellar bile salt concentration. The relationship between intermicellar bile salt concentration and micellar bile salt/phospholipid, defined in the dilution studies, was linear in the range of study. For a composite of five biles, this relationship was described by the equation: intermicellar bile salt concentration = 1.27 (bile salt/phsopholipid) + 0.538. Data obtained on an artificial bile agreed closely with the results obtained on bile suggesting that the other constituents of bile did not affect this analysis. These findings may be helpful in understanding the process of micellar cholesterol solubilization in bile.

Bile↗
PubMed2000

Bile acids in xenogeneic ex-vivo liver perfusion: function of xenoperfused livers and compatibility with human bile salts and porcine livers.

BACKGROUND: In recent years, hepatic support systems using xenogeneic cells have been developed to support patients in fulminant hepatic failure. The extent to which xenogeneic hepatocytes metabolize and excrete human organic anions is unclear. In these studies we examined the ability of the ex vivo porcine liver to clear human bile acids during extracorporeal liver perfusion (ELP). METHODS: Four patients with fulminant hepatic failure underwent extracorporeal liver perfusion with 9 porcine livers. The venovenous circuit was designed as previously described (NEJM,1994,331:234) as were the immunologic features (Transplantation 1994,58:1162). Bile from the porcine liver and serum samples were collected hourly during perfusion. Three bile acids (glycocholic, glycodeoxycholic, taurodeoxycholic acid) were selected as markers for human bile and three (glycohyocholic, glycohyodeoxycholic, and glyco-3alpha-hydroxy-6-oxo-5beta-cholanoic acid) for markers of pig bile. Bile acids from both serum and bile were processed and analyzed through high performance liquid chromatography. The Students' t test was used for statistical analysis. RESULTS: The mean duration of perfusions was 4.1+/-1.5 hr. The mean total bile acid clearance from serum (243+/-44 micromol/h) was similar to the total bile acid biliary excretion (286+/-84 micromol/hr, P = 0.06). After 1 hr of perfusion, bile samples demonstrated a predominance of pig bile salts (65%). After 3 hr of perfusion, human bile acids made up 85% of total biliary bile acids. Pig bile acids appeared in patients' sera after 1 hr of perfusion, and after 3 hr, 35% of serum bile salts were pig-specific. CONCLUSIONS: Porcine livers perfused with human blood can clear the serum of potentially toxic human bile acids and excrete them into bile. Simultaneously, the percentage of pig-specific bile acids in patient serum increases during xenogeneic perfusion for unknown reasons. The relative hepatic uptake of bile acid from serum is similar to bile acid excretion in bile. Further development of systems using porcine livers or hepatocytes is warranted.

Animals↗
PubMed1997

Does bile spillage during an operation present a risk for peritoneal metastasis in bile duct carcinoma?

Whether bile spillage during operation presents a risk for peritoneal metastasis in the treatment of bile duct carcinoma was studied in 15 patients (12 with bile duct cancer, 3 with cancer of the papilla of Vater) who had all undergone a pancreatoduodenectomy. Preoperative bile was sampled through a percutaneous transhepatic biliary drainage catheter. Nine patients with bile duct cancer and one with cancer of the papilla of Vater showed positive bile cytology. The operative bile was obtained at the hepatic duct stump after a resection of the tumor-bearing bile duct. The operative bile in 10 patients with positive preoperative bile was found to be positive, while that in the five patients with negative preoperative bile was negative. Thus, the specificity of operative bile was identified as 100%. Moreover, in five patients with preoperative positive bile, saline irrigation of intrahepatic bile duct after a full recovery of hepatic bile revealed cancer cells to remain in the intrahepatic biliary trees. The viability of preoperative bile was 61%-97% with 1 x 10(4)-2.4 x 10(5) tumor cells, whereas there was a 41%-97% viability with 7.6 x 10(4)-10.4 x 10(5) tumor cells in the operative or irrigated bile. Accordingly, the patients with preoperative positive bile are thus suggested to be at high risk of inducing peritoneal metastasis due to the inadvertent spillage of hepatic bile at the time of resection of a bile duct tumor.

Adenocarcinoma↗
PubMed1986

Bile acid structure and bile formation in the guinea pig.

The effects of intravenous infusions (1-4 mumol/min/kg) of 14 bile acids, cholic, deoxycholic, ursodeoxycholic, chenodeoxycholic, dehydrocholic, and their glycine and taurine conjugates, on bile flow and composition and on the biliary permeation of inert carbohydrates have been studied in the guinea pig bile fistula. Hydroxy bile acids were eliminated in bile without major transformation, except for conjugation (over 90%) when unconjugated bile acids were infused. During infusion of dehydrocholate and taurodehydrocholate, 77-100% of the administered dose was recovered in bile as 3-hydroxy bile acids, thus indicating that reduction of the keto group in position 3 was virtually complete. All bile acids produced choleresis at the doses employed: the strongest choleretic was deoxycholate (81.78 microliters/mumol), the weakest was taurodehydrocholate (10.2 microliters/mumol). Choleretic activity was directly and linearly related to bile acid hydrophobicity, as inferred by HPLC, both for similarly conjugated bile acids, and for bile acids having the same number, position, or configuration of the hydroxyl groups. In all instances, the rank ordering was: deoxycholate greater than chenodeoxycholate greater than cholate greater than ursodeoxycholate. During choleresis produced by any of the bile acids tested, bicarbonate concentration in bile slightly declined, but the calculated concentration in bile-acid-stimulated bile (45-57 mmol/l) was always higher than that measured in plasma (23-26 mmol/l). Biliary concentrations of cholesterol (20-68 mumol/l) and phospholipid (14-63 mumol/l) were very low during spontaneous secretion, and declined even further following bile acid choleresis. None of the infused bile acids consistently modified biliary excretion of cholesterol and phospholipid. Consistent with a previous observation from this laboratory, all hydroxy bile acids reversibly diminished [14C]erythritol and [14C]mannitol biliary entry during choleresis, while they increased or failed to modify that of [3H]sucrose and [3H]inulin. The rank ordering for the inhibitory effect on [14C]erythritol and [14C]mannitol permeation was: 3 alpha,7 alpha,12 alpha-trihydroxy greater than 3 alpha,7 alpha-dihydroxy greater than 3 alpha,7 beta-dihydroxy greater than 3 alpha,12 alpha-dihydroxy bile acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1976

The contribution of the extrahepatic bile ducts to bile formation.

This study was performed to determine the contribution of the extrahepatic bile ducts to bile flow in the rhesus monkey. Bile flow from the two sides of the liver was divided. The major extrahepatic bile ducts remained connected to one side of the liver only. Bile flow, and the concentrations of [14C]erythritol, bicarbonate, bile acid, and bilirubin in bile samples from the two sides of the liver, in the fed state were measured and compared. An estimate of the net flow from the extrahepatic ducts was obtained from the [14C]-erythritol concentrations on the two sides of the liver and the bile flow rate on the side with the extrahepatic ducts. The [14C]erythritol bile-plasma ratio was significantly lower in bile collected from the side with the extrahepatic bile ducts, than in bile from the other side of the liver. About 10% of total hepatic bile flow originated in the extrahepatic bile ducts, in the fed state. The bicarbonate-[14C]erythritol concentration ratio was significantly higher in bile from the side with the extrahepatic bile ducts. Bicarbonate - bile acid, and bicarbonate-bilirubin concentration ratios were also significantly higher in bile from the side of the liver with the extrahepatic ducts. The extrahepatic bile ducts have a physiologically significant role in the secretion of bile water. Bicarbonate is secreted in association with water in the extrahepatic ducts.

Animals↗
PubMed1988

Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile.

A detailed study of the qualitative and quantitative composition of bile acids in human fetal gallbladder bile is described. Bile was collected during early gestation (weeks 16-19) and analyzed by gas chromatography and mass spectrometry, fast atom bombardment ionization mass spectrometry, and high performance liquid chromatography. Bile acids were separated into different conjugate groups by chromatography on the lipophilic anion exchange gel, diethylaminohydroxypropyl Sephadex LH-20. Quantitatively more than 80% of the bile acids were secreted into bile conjugated to taurine. Unconjugated bile acids and glycine conjugates accounted for 5-10% of the total biliary bile acids. Bile acid sulfates were present only in trace amounts indicating that quantitatively sulfation is not an important pathway in bile acid metabolism during development. Total biliary bile acid concentrations were low (0.1-0.4 mM) when compared to reported values for adult bile (greater than 10 mM). Chenodeoxycholic acid was the major biliary bile acid and exceeded cholic acid concentrations by 1.43-fold indicating either a relative immaturity in 12 alpha-hydroxylase activity during early life or a dominance of alternative pathways for chenodeoxycholic acid synthesis. A relatively large proportion of the biliary bile acids comprised metabolites not found in adult bile. The presence of relatively high proportions of hyocholic acid (often greater than cholic acid) and several 1 beta-hydroxycholanoic acid isomers indicates that C-1 and C-6 hydroxylation are important pathways in bile acid synthesis during development. We describe, for the first time, evidence for the existence of a C-4 hydroxylation pathway in the metabolism of bile acids, which may be unique to early human development. Mass spectrometry was used to confirm the identification of 3 alpha,4 beta,7 alpha-trihydroxy-5 beta-cholanoic and 3 alpha,4 beta-dihydroxy-5 beta-cholanoic acids. Quantitatively, these C-4 hydroxylated bile acids accounted for 5-15% of the total biliary bile acids of the fetus, suggesting that C-4 hydroxylation is quantitatively an important pathway in the bile acid metabolism during early life.

Bile↗
PubMed1974

The control of bile acid pool size: effect of jejunal resection and phenobarbitone on bile acid metabolism in the rat.

In patients with cholesterol gallstones, there is a diminished bile acid pool and the bile becomes supersaturated with cholesterol. Medical treatment has been aimed at re-expanding the pool to improve cholesterol solubility in bile but as yet the factors controlling the size of the bile acid pool' are unknown. Therefore the role of the liver and intestine in controlling bile acid pool size in the rat was studied and the effect of experimental expansion of the pool on bile acid metabolism and bile lipid composition examined. Bile acid absorption was increased from ileum made hyperplastic by previous jejunectomy and hepatic bile acid synthesis was increased by phenobarbitone treatment. Both jejunal resection and phenobarbitone significantly increased the size of the bile acid pool from 32.2 +/- SEM 0.94 mumoles/100 g body weight to 42.2 +/- 1.71 and 44.4 +/- 2.03 respectively. However, the effects of these experimental manipulations on bile acid secretion rate, enterohepatic cycling frequency, and synthesis rates were quite different. Jejunectomy caused a 56% increase in bile acid secretion and more rapid cycling of the bile acid pool but the enhanced absorption did not depress bile acid synthesis. In contrast, phenobarbitone markedly increased synthesis from 14.5 +/- 1.42 mumoles.100 g BW(-1). 24 hr(-1) to 25.9 +/- 3.19 but there was no significant change in bile acid secretion and the choleresis seen after phenobarbitone was mainly due to an increase in the bile acid-independent fraction of bile flow. In these experimental studies in the rat, expansion of the bile acid pool did not significantly change bile lipid composition or cholesterol solubility in bile.

Animals↗