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At least 451 records · Page 25Linked to original sources
PubMed1986

Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids.

Hypertransaminasemia is a frequent side effect during chenodeoxycholic administration for gallstone dissolution. Evidence suggests that this effect is not mediated by lithocholic acid, the intestinal metabolite of chenodeoxycholic acid, but that toxicity is due to the chenodeoxycholic acid itself. In vitro cytotoxicity of bile salts is positively proportional to their detergent effect, which is, on the other hand, related to their hydrophobic-hydrophilic balance. We hypothesize that in vivo also liver injury can occur when the liver is perfused by an high proportion of strongly detergent bile salts. The more detergent bile salts are unconjugated or glycine conjugated, while the lesser are taurine conjugated and sulfated. Within each class the following order of decreasing detergent power can be indicated: lithocholic greater than deoxycholic greater than chenodeoxycholic greater than cholic greater than ursodeoxycholic acid. Besides chronic exogenous administration of chenodeoxycholic or deoxycholic acids, conditions in which the liver is perfused by an high mass of highly detergent bile salts are those characterized by an enhanced intestinal biodegradation of bile salts. These conditions, which are common features of some chronic inflammatory bowel diseases, are frequently associated with liver damage. On the other hand, a normally detergent bile salt pool can become hepatotoxic for liver cells which have already been injured. In this respect, as already reported for increased sulfation, the increased proportion of taurine conjugates and the reduced formation of deoxycholic acid in liver cirrhosis can be regarded as protective mechanisms. Liver toxicity induced by bile salts' detergent action can be prevented by favouring tauroconjugation or reducing the intestinal degradation of bile salts or by administering poorly detergent bile salts.

Alanine Transaminase↗
PubMed2005

Adaptative bile duct proliferative response in experimental bile duct ischemia.

BACKGROUND/AIMS: A rat model of bile duct ischemia was established and used to examine the potential of bile duct proliferation to provide an adaptative response in cholestatic disorders. METHODS: Rats underwent partial or complete arterial deprivation of the liver. Serum biochemical tests, histological analyses and bile secretion measurements were performed at different time points up to 6 weeks after surgery. RESULTS: Rats developed biochemical signs of cholestasis exclusively after complete arterial deprivation. Within 4h, cholangiocytes in these rats showed morphological signs of cell damage. After 48h, they displayed VEGF expression and became proliferative. The proportion of Ki67-labeled cholangiocytes ( approximately 30%) was similar in interlobular bile ducts and periportal ductules. A ductular reaction made of well-formed bile ducts confined to portal tracts developed within 1 week. Bile flow which was initially decreased, was restored at 3 weeks, while the biochemical signs of cholestasis completely resolved at 6 weeks. At this time, the number of bile duct sections was maximal. Fibrosis intensity was also maximal, although moderate (<F2 METAVIR staging) as assessed by Sirius-red staining morphometry. CONCLUSIONS: In the present model of bile duct ischemia, ductular reaction derives from bile ducts of all anatomical compartments, and provides a poorly fibrogenic functional response to biliary dysfunction.

Animals↗
PubMed1993

Effects of bile acids and taurine on the lipid fluidity of hepatic microsomes in normal and bile duct-ligated rats--a spin label study.

In cholestasis and obstructive jaundice, hepatic bile acids and taurine content increase significantly and bile acids change in compositions. For example, increases in cholic acid, beta-muricholic acid and taurine-conjugated bile acids occur in rats. In this study, to clarify the significance of changes in bile acid composition in obstructive jaundice, the effects of various bile acids and taurine on the fluidity of the hepatic microsomal membrane were studied by the electron spin resonance spin-label method in normal and bile duct-ligated (for 10 days) rats. The flow properties (order parameter) of the shallow and deep layers of the membrane were determined with 5- and 12-doxyl stearic acid, respectively. Bile acids mainly affected the fluidity of the shallow membrane layer. The fluidity of the hepatic microsomal membrane was decreased in bile duct-ligated rats. Conjugated cholic acid (taurine-conjugated cholic acid, glycine-conjugated cholic acid and non-conjugated beta-muricholic acid exerted effects that increased fluidity in comparison with non-conjugated cholic acid and chenodeoxycholic acid, a precursor of beta-muricholic acid. Taurine had no clear effect on fluidity. In conclusion, cholic acid conjugation and beta-muricholic acid formation may be mechanisms which protect against the decrease in lipid fluidity of hepatic biomembranes in cholestasis or obstructive jaundice. Taurine may also affect fluidity through the formation of taurine-conjugated bile acids.

Animals↗
PubMed2004

Everolimus/cyclosporine interactions on bile flow and biliary excretion of bile salts and cholesterol in rats.

As a possible explanation for everolimus/cyclosporine-induced hypercholesterolemia seen in transplant recipients, we investigated the interactions of the immunosuppressants everolimus and cyclosporine on bile flow and biliary excretion of bile salts and cholesterol in a subchronic bile fistula model in rats because biliary excretion is a main elimination route of cholesterol. After 2 weeks of daily treatment, everolimus (1 mg/kg i.p.) and cyclosporine (5 mg/kg i.p) decreased bile flow (-45 and -36%) and biliary excretion of bile salts (-34 and -54%) and cholesterol (-25 and -39%) and increased serum concentrations of cholesterol (+40 and +17%) and triglycerides (+220 and +110%). Bile salt serum concentration was elevated only by cyclosporine (+100%), and not by everolimus. Everolimus/cyclosporine slightly enforced the cyclosporine-induced hyperlipidemia but not reduction of bile parameters, while the cyclosporine-induced increase in bile salts in serum was totally prevented. From these results we conclude that bile salt synthesis could be impaired by everolimus, which could be one reason for everolimus-induced hypercholesterolemia.

Animals↗
PubMed1992

Cell swelling increases bile flow and taurocholate excretion into bile in isolated perfused rat liver.

The effects of aniso-osmotically and amino-acid-induced cell-volume changes on bile flow and biliary taurocholate excretion were studied in isolated perfused rat liver. With taurocholate (100 microM) in the influent perfusate, hypo-osmotic exposure (225 mosmol/l) increased taurocholate excretion into bile and bile flow by 42 and 27% respectively, whereas inhibition by 32 and 47% respectively was observed after hyperosmotic (385 mosmol/l) exposure. The effects of aniso-moticity on taurocholate excretion into bile was observed throughout aniso-osmotic exposure, even after completion of volume-regulatory ion fluxes and were fully reversible upon re-exposure to normo-osmotic media. Hypo-osmotic cell swelling (225 mosmol/l) increased the Vmax. of taurocholate translocation from the sinusoidal compartment into bile about 2-fold. Also, cell swelling induced by glutamine and glycine stimulated both bile flow and biliary taurocholate excretion. There was a close relationship between the aniso-osmotically and amino-acid-induced change of cell volume and taurocholate excretion into bile. The data suggest that liver cell volume plays an important role in regulating bile-acid-dependent bile flow and biliary taurocholate excretion.

Amino Acids↗
PubMed2000

Importance of arginines 63 and 423 in modulating the bile salt-dependent and bile salt-independent hydrolytic activities of rat carboxyl ester lipase.

Previous studies using chemical modification approach have shown the importance of arginine residues in bile salt activation of carboxyl ester lipase (CEL) activity. However, the x-ray crystal structure of CEL failed to show the involvement of arginine residues in CEL-bile salt interaction. The current study used a site-specific mutagenesis approach to determine the role of arginine residues 63 and 423 in bile salt-dependent and bile salt-independent hydrolytic activities of rat CEL. Mutations of Arg(63) to Ala(63) (R63A) and Arg(423) to Gly(423) (R423G) resulted in enzymes with increased bile salt-independent hydrolytic activity against lysophosphatidylcholine, having 6.5- and 2-fold higher k(cat) values, respectively, in comparison to wild type CEL. In contrast, the R63A and R423A mutant enzymes displayed 5- and 11-fold decreases in k(cat), in comparison with wild type CEL, for bile salt-dependent cholesteryl ester hydrolysis. Although taurocholate induced similar changes in circular dichroism spectra for wild type, R63A, and R423G proteins, this bile salt was less efficient in protecting the mutant enzymes against thermal inactivation in comparison with control CEL. Lipid binding studies revealed less R63A and R423G mutant CEL were bound to 1,2-diolein monolayer at saturation compared with wild type CEL. These results, along with computer modeling of the CEL protein, indicated that Arg(63) and Arg(423) are not involved directly with monomeric bile salt binding. However, these residues participate in micellar bile salt modulation of CEL enzymatic activity through intramolecular hydrogen bonding with the C-terminal domain. These residues are also important, probably through similar intramolecular hydrogen bond formation, in stabilizing the enzyme in solution and at the lipid-water interface.

Animals↗
PubMed2004

The role of alpha1-fetoprotein transcription factor/LRH-1 in bile acid biosynthesis: a known nuclear receptor activator that can act as a suppressor of bile acid biosynthesis.

Two key regulatory enzymes in the bile acid biosynthesis pathway are cholesterol 7alpha-hydroxylase/CYP7A1 (7alpha-hydroxylase) and sterol 12alpha-hydroxylase/CYP8B1 (12alpha-hydroxylase). It has been shown previously that hepatocyte nuclear factor-4alpha (HNF-4) and the alpha(1)-fetoprotein transcription factor (FTF) are activators of 7alpha-and 12alpha-hydroxylase transcription and that the small heterodimer partner (SHP) suppresses bile acid biosynthesis by heterodimerizing with FTF. However, the role of FTF in bile acid biosynthesis has been studied only in tissue culture systems. In heterozygous FTF knockout mice, 7alpha- and 12alpha-hydroxylase genes were expressed at 5-7-fold higher levels than in wild-type mice, an apparent direct contradiction to previous in vitro observations. This higher expression of the 7alpha- and 12alpha-hydroxylase genes resulted in a 33% higher bile acid pool in their gallbladders, bile more enriched in cholic acid, and a 13% decrease in plasma cholesterol levels. Adenovirus-mediated FTF overexpression in wild-type mice resulted in 10-fold lower expression of the 7alpha- and 12alpha-hydroxylase genes and up to 8-fold higher SHP expression, highlighting the dual role that FTF plays in different promoters. Shorter overexpression times still resulted in lower 7alpha- and 12alpha-hydroxylase expression, but unchanged SHP expression, suggesting that two different mechanisms are involved in the FTF-mediated suppression of 7alpha- and 12alpha-hydroxylase expression. This FTF-mediated suppression of the expression of two bile acid biosynthesis genes resulted in a 3-fold lower rate of bile acid synthesis in a rat bile fistula animal model. Based on these observations and on protein binding studies performed in vitro and by chromatin immunoprecipitation, we hypothesize that FTF has two synergetic effects that contribute to its role in bile acid biosynthesis: 1) it has the ability to activate the expression of SHP, which in turn heterodimerizes and suppresses FTF transactivation activity; and 2) it occupies the FTF/HNF-4 recognition site within the 7alpha- and 12alpha-hydroxylase promoters, which can otherwise be occupied by a factor (HNF-4) that cannot be suppressed by SHP.

Animals↗
PubMed2001

Effect of the diameter of the common bile duct on the incidence of bile duct stones in patients with recurrent attacks of right epigastric pain after cholecystectomy.

OBJECTIVE: To study the relationship between the diameter of the common bile duct and the incidence of bile duct stones in non-jaundiced patients with recurrent attacks of right epigastric pain after cholecystectomy. DESIGN: Retrospective study. SETTING: University hospital, Finland. SUBJECTS: 57 consecutive, non-jaundiced patients admitted for elective endoscopic retrograde cholangiopancreatography (ERCP) because of attacks of right epigastric pain after cholecystectomy. INTERVENTIONS: Measurement of maximum diameter of the common bile duct and presence or absence of bile duct stones. MAIN OUTCOME MEASURES: Diameter of bile duct (10 mm or less was regarded as normal) and presence or absence of stones. RESULTS: 33 patients had normal-sized bile ducts and in 24 they were widened. Only 2/33 patients with normal-sized ducts (6%) had stones, compared with 11/24 (46%) with wide ducts (p = 0.0008). However, the degree of ductal dilatation did not seem to have any influence on the presence or absence of stones. CONCLUSION: Bile duct stones are unlikely after cholecystectomy in patients who are not jaundiced and have a normal-sized common bile duct. However, nearly half of the patients with a wide common bile duct had stones, but the degree of dilatation was not important.

Abdominal Pain↗
PubMed1996

Analysis of bile acids in urine specimens from healthy humans: determination of several bile acids with beta-hydroxyl and carbonyl groups.

Urinary bile acids of 39 healthy male undergraduates were analyzed by capillary gas chromatography and capillary gas chromatography-mass spectrometry. 3 alpha-Hydroxy-12-oxo-5 beta-cholanoic acid, 3 alpha, 12 beta-dihydroxy-5 beta-cholanoic acid, 3 beta, 7 alpha-dihydroxy-5 beta-cholanoic acid, and 3 alpha, 7 alpha, 12 beta-trihydroxy-5 beta-cholanoic acid, in addition to known bile acids, were identified and then quantified. The major part of the urinary bile acids was occupied by secondary bile acids. Every 7 beta-hydroxylated bile acid species was found in more than 80% of the subjects. The bile acid detected in the largest amount was 3 alpha-hydroxy-12-oxo-5 beta-cholanoic acid. The metabolites of cholic acid were quantitatively more predominant than those of chenodeoxycholic acid. These results indicate that bile acids with beta-hydroxyl and carbonyl groups at the C-3,7 and/or 12 positions are usual bile acids usually found in the urine of healthy humans. It is concluded that the occurrence of these bile acids is an effect of the intestinal bacterial flora and living conditions.

Adult↗
PubMed1986

Bile alcohol profiles in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis.

Bile alcohols in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis have been analyzed by a combination of capillary gas-liquid chromatography and mass spectrometry after fractionation into groups according to mode of conjugation. The presence of at least 18 bile alcohols, which were excreted mainly as glucurono-conjugates in bile and urine, and as unconjugated forms in feces, was demonstrated. The following bile alcohols were identified with certainty by direct comparison with reference compounds: 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol; (23R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,23-tetrol; 5 alpha- and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24-tetrols; 5 alpha- and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrols; 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol; (22R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,22,25-pentol; (23R)- and (23S)-5 beta-cholestane-3 alpha,7 alpha, 12 alpha,23,25-pentols; 3 alpha,12 alpha,25-trihydroxy-5 beta-cholestane-7-one; (24R)- and (24S)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentols; 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol. Although the bile alcohol profile in urine was quite different from those in bile and feces, the determination of urinary bile alcohols as well as of biliary and fecal bile alcohols could be used for diagnosis of cerebrotendinous xanthomatosis.

Adult↗
PubMedDate not supplied

Hydrophilic bile salts and liposomes inhibit hydrophobic bile salt-induced release of glycoprotein by guinea-pig gall-bladder.

Bile salts can be cytotoxic to mucosal surfaces, because of their detergent properties. This is not normally seen under physiological circumstances in the gall-bladder. To further study normal mucosal defence mechanisms, the present study was performed to examine the effects of liposomes and hydrophilic bile salts on hydrophobic bile salt-induced release of radiolabelled glycoproteins from explants of guinea-pig gall-bladder. Glycoprotein release was correlated with the degree of hydrophobicity of bile salts, as determined by the retention factor in reversed-phase high-performance liquid chromatography. Hydrophobic bile salt-induced release of glycoproteins was reduced by liposomes and hydrophilic bile salts. The inhibitory effect of liposomes was directly related to the degree of saturation of their fatty acyl chains, and that of hydrophilic bile salts was related to the degree of hydrophilicity. These findings suggest that vesicles and hydrophilic bile salts may play a cytoprotective role against membrane damage passively caused by hydrophobic bile salts in the biliary system, and that such damage may occur according to the quantitative and qualitative imbalance among these factors.

Animals↗
PubMed2005

A tissue-engineered artificial bile duct grown to resemble the native bile duct.

The aim of this study was to fabricate an artificial bile duct for the development of a new treatment for biliary diseases. Eighteen hybrid pigs were implanted with a bile duct organoid unit (BDOU) made of a bioabsorbable polymer. Twelve of the transplanted BDOUs had been seeded with autologous bone marrow cells (BMCs) in advance. Six animals, the controls, were grafted with the scaffold alone with no BMCs seeded. The common bile duct was cut, the hepatic cut end of the native common bile duct was anastomosed to the BDOU and the other end was anastomosed to the duodenum. The controls underwent a similar operation. The neo-bile duct was removed at pre-determined time points and investigated histologically. All 18 recipient pigs survived until their sacrifice at 6 weeks, 10 weeks or 6 months. Histological examination revealed incomplete epithelialization of the neo-bile duct at 6 weeks and 10 weeks after transplantation. At 6 months, the organoid exhibited a morphology almost identical to that of the native common bile duct. No differences were found between the controls and BMC-seeded pigs. These results show that the artificial bile duct thus fabricated can serve as a substitute for the native bile duct.

Absorbable Implants↗
PubMed1992

The bile acid-inducible baiB gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A ligase.

The baiB gene from Eubacterium sp. strain VPI 12708 was previously cloned, sequenced, and shown to be part of a large bile acid-inducible operon encoding polypeptides believed to be involved in bile acid 7 alpha-dehydroxylation. In the present study, the baiB gene was subcloned and expressed in Escherichia coli and shown to encode a bile acid-coenzyme A (CoA) ligase. This ligase required a C-24 bile acid with a free carboxyl group, ATP, Mg2+, and CoA for synthesis of the final bile acid-CoA conjugate. Product analysis by reverse-phase high-performance liquid chromatography revealed final reaction products that comigrated with cholyl-CoA and AMP. A putative bile acid-AMP intermediate was detected when CoA was omitted from the reaction mixture. The bile acid-CoA ligase has amino acid sequence similarity to several other polypeptides involved in the ATP-dependent linking of AMP or CoA to cyclic carboxylated compounds. The bile acid-CoA ligation is believed to be the initial step in the bile acid 7 alpha-dehydroxylation pathway in Eubacterium sp. strain VPI 12708.

Base Sequence↗
PubMed2004

Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR alpha activation favors the formation of unconjugated bile acids.

In human liver, unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion, whereas the accumulation of unconjugated bile acids may become hepatotoxic. We hypothesized that the formation of unconjugated and conjugated bile acids from their common substrate bile acid-CoA thioesters by BACTE and BACAT is regulated via the peroxisome proliferator-activated receptor alpha (PPARalpha). Livers from wild-type and PPARalpha-null mice either untreated or treated with the PPARalpha activator WY-14,643 were analyzed for BACTE and BACAT expression. The total liver capacity of taurochenodeoxycholate and taurocholate formation was decreased in WY-14,643-treated wild-type mice by 60% and 40%, respectively, but not in PPARalpha-null mice. Suppression of the peroxisomal BACAT activity was responsible for the decrease in liver capacity, whereas cytosolic BACAT activity was essentially unchanged by the treatment. In both cytosol and peroxisomes, the BACTE activities and protein levels were upregulated 5- to 10-fold by the treatment. These effects caused by WY-14,643 treatment were abolished in PPARalpha-null mice. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARalpha activation.

Acyltransferases↗
PubMed1982

Interaction of insulin, glucagon, and DBcAMP on bile acid-independent bile production in the rat.

In experiments on fasted, pentobarbital-anesthetized rats the effect of insulin (1 U X kg-1, followed by 0.05 U X kg-1 X min-1), glucagon (0.5 micrograms X kg-1 X min-1), and dibutyrylic cyclic AMP (DBcAMP) (0.5 mumol X kg-1 X min-1) on bile flow and composit8ion was examined. Infusion of these substances resulted in maximal increases only in the bile acid-independent bile formation, and insulin appeared to be a more powerful stimulant of bile production than glucagon or DBcAMP. When bile production was first stimulated maximally with glucagon or DBcAMP, supplementary infusion of insulin increased bile production significantly. When administration of glucagon or DBcAMP supplemented maximal infusion of insulin, only DBcAMP resulted in a further increase in bile production. Bile production was, however, increased by supplementary glucagon infusion, when a submaximal dosage of insulin was given. No additive effect of glucagon and DBcAMP on bile secretion was observed. The results suggest that glucagon induces choleresis in rats via liberation of cAMP and that the mechanisms of glucagon choleresis differ at least partly from those involved in insulin choleresis. The results are compatible with an insulin-produced inhibition of the adenylate cyclase and activation of the phosphodiesterase in the liver. In accordance with present knowledge of the biological effects of insulin and glucagon the choleretic response to both hormones may be secondary to stimulation of Na-K-ATPase located to the hepatocellular membrane.

Animals↗
PubMed1989

Identification of bile alcohols in rat bile.

Bile alcohols in rat bile were analyzed by gas-liquid chromatography-mass spectrometry. Six bile alcohols were newly identified as minor constituents in addition to 5 beta-cholestane-3 alpha,7 alpha,12 alpha,26-tetrol, major bile alcohol of rat bile. The bile alcohols newly identified were 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol, 5 alpha-cholestane-3 alpha,7 alpha,12 alpha,26-tetrol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,26-pentol, 5 alpha-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol, and 5 beta-cholestane-3 alpha,6 beta,7 beta,25,26-pentol. The biliary bile alcohols of the rat occurred mainly as the sulfuric acid esters and, in lesser amounts, as glucuronoconjugated and unconjugated forms. The amount of total bile alcohols was about 27.9 nmol in 1 ml of bile.

Animals↗
PubMed1982

Response of total and individual serum bile acids to endogenous and exogenous bile acid input to the enterohepatic circulation.

The response of total nonsulfated serum bile acids, cholylglycine, and chenodeoxycholyl species was examined every 20 min for 3 h in 6 subjects. Noncaloric feeding led to a progressive decline or no change in bile acids, while there was a progressive rise in response to a standard liquid meal. After reaching a peak at 60 min, total bile acids declined progressively but cholylglycine and chenodeoxycholyl species remained elevated. Continuous infusion of cholecystokinin led to significantly greater levels most probably due to more rapid enterohepatic recirculation. Oral administration of 250 mg of chenodeoxycholic acid with water resulted in a rise in total bile acids and chenodeoxycholyl species, but not cholylglycine, indicating the rise was due to the administered bile acid and not gallbladder contraction. Administration of a meal and chenodeoxycholic acid simultaneously caused no greater rise of total serum bile acids or cholylglycine than either stimulus alone. Peak response and area under the curve were compared for each patient. The increase for chenodeoxycholyl species was additive for the two stimuli, suggesting that free chenodeoxycholic acid, when administered with a meal, decreased the absorption of endogenous conjugated bile acids. This study is compatible with the thesis that serum bile acids accurately reflect enterohepatic cycling and that administration of chenodeoxycholic acid with a meal may decrease its efficacy because exogenous chenodeoxycholic acid may compete with endogenous bile acids for absorption.

Adult↗
PubMed1980

Developmental pattern of bile acid metabolism as revealed by bile acid analysis of meconium.

The developmental metabolism of bile acids can be partly studied by the analysis of bile acid patterns in meconium. Employing modern analytical techniques, it has been found that besides the main bile acids of humans (cholic, chenodexoycholic, deoxycholic, and lithocholic acids) several "atypical" bile acids occur in meconium. It is unlikely that these "atypical+ bile acids are derived from materno--fetal transfer, and they therefore probably reflect a special fetal bile acid metabolism. Hydroxylations at positions 1 and 6 of the steroid skeleton are regularly encountered. These hydroxylations, as well as the occurrence of 3 beta-hydroxy-delta 5 compounds and of bile acids of the 5 alpha series, suggest that fetal bile acid synthesis differs markedly from that of the adult. These observations are of interest in relation to the origin of unusual bile acids found in the cholestatic condition of the adult. It appears that a resurgence of the fetal biosynthetic patterns takes place under the conditions of cholestatic liver disease.

Bile Acids and Salts↗