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PubMed2002

Rapid and improved method for the determination of bile acids in human feces using MS.

A simple method for the determination of bile acids in adult human fecal samples using GC-MS is described. Bile acids are directly extracted from feces by ethanol (95%) containing 0.1 N NaOH. Extracts are purified by passage through a reversed-phase C18 silica cartridge and then analyzed by GC-MS. The present study has shown that lyophilized human feces contain mainly free bile acids, with lithocholic acid (LCA) and deoxycholic acid (DCA) as the major bile acids; however, isomers of LCA and DCA, keto-bile acids, and cholic acid are also present. Any traces of conjugated bile acids are hydrolyzed before the C18 extraction by deconjugating enzymes, which are present in feces and are activated by the addition of water during the homogenization step. Thus, the analysis of fecal bile acids can be performed without the hydrolysis step in less than 4 h in comparison to traditional techniques, which usually require at least 48 h.

Adult↗

PubMed1982

Uptake of bile acids by isolated rat hepatocytes.

Hepatic uptake of five common bile acids was examined in isolated rat hepatocytes. Taurocholic acid (TCA), glycocholic acid (GCA), cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were studied. Uptake was extremely rapid and was linear for at least 45 sec for all bile acids tested at substrate concentrations from 1 to 400 micrometers. Both nonsaturable binding to the cell surface membrane and the initial rate of uptake (V0) of the dihydroxy bile acids (DCA and CDCA) were about ten times greater than those of the trihydroxy bile acids (TCA, GCA and CA) which correlates with the higher lipophilicity of the dihydroxy bile acids. Kinetic analysis demonstrated that uptake of these bile acids was due both to a saturable process and a linear process. The apparent diffusion constant (Dapp) of the unsaturable process for the dihydroxy bile acids was also ten times greater than that for the trihydroxy bile acids. After correction for the nonsaturable binding to the cell membrane and linear entry, the Km and Vmax for the uptake was determined. Conjugation with taurine decreased the Km of CA but not the Vmax, while glycine conjugation did not alter either parameter, suggesting that conjugation with taurine may increase its affinity for the transport system. The trihydroxy bile acids have a higher affinity but a lower transporting capacity for the saturable process than the dihydroxy bile acids. In vivo hepatic extraction appears to be more dependent on the affinity of the bile acid for the transport system than the capacity at which it can be transported.

Animals↗

PubMed1985

Bile acid binding in plasma: the importance of lipoproteins.

Bile acid (BA) hydrophobicity, evaluated by the octanol-water partition coefficient, decreases along the series deoxycholic acid-chenodeoxy cholic acid-hyodeoxycholic acid-ursodeoxycholic acid-cholic acid (CA)-ursocholic acid (UCA). In vitro experiments carried out using dialysis techniques (to determine the maximum BA binding) and ultrafiltration of plasma pre-incubated with 0.1 mM BA (to assess the distribution of BA between the different lipoprotein fractions) showed that the maximum binding of BA to plasma and lipoproteins follows the same order of hydrophobicity. The fraction not bound to proteins, greater with the hydrophilic BA (UCA and CA), is distributed in the lipoprotein fractions and in particular in high density lipoproteins.

1-Octanol↗

PubMed1988

Kinetics for the synthetic bile acid 75selenohomocholic acid-taurine in humans: comparison with [14C]taurocholate.

The "apparent" fractional turnover rate of the gamma-labeled bile acid analogue 75selenohomocholic acid-taurine (75SeHCAT) was assessed from decline in radioactivity over the gallbladder area on 4 successive days using a gamma-camera, and was compared in the same subjects with the fractional turnover rate of the corresponding natural bile acid, cholic acid-taurine, labeled with 14C ([14C]CAT) using the classical Lindstedt technique. Very similar results were obtained in 5 healthy individuals (coefficient of variation 4.8%, medians 0.35 and 0.34, respectively). By contrast, the fractional deconjugation rate assessed from zonal scanning of glycine- and taurine-conjugated bile acids on thin-layer chromatography was much less for 75SeHCAT than for [14C]CAT (0.02 and 0.13, respectively; p less than 0.05). The fractional rate for deconjugation plus dehydroxylation was also determined by zonal scanning, and gave lower values for 75SeHCAT than for [14C]CAT (0.02 and 0.12, respectively; p less than 0.05). There was a striking similarity between the fractional rate for deconjugation alone and that for deconjugation plus dehydroxylation for both bile acids in individual samples (r = 0.999, p less than 0.001), suggesting that these two processes might occur simultaneously and probably involve the same bacteria. We conclude that our scintiscanning technique provides an accurate, noninvasive method of measuring fractional turnover rate of a bile acid in humans, and that the finding that 75SeHCAT remains conjugated with taurine during enterohepatic recycling means that absorption should be specific for the ileal active transport site, thus rendering it an ideal substance for assessing ileal function.

Abdomen↗

PubMed1983

Effects of jejunoileal bypass on the enterohepatic circulation of bile acids, bacterial flora in the upper small intestine, and absorption of vitamin B12.

Eleven morbidly obese patients were studied before and at various time intervals after jejunoileal bypass (JIB). Bile acid deconjugation was assessed with the bile acid breath test and bile acid absorption by analyzing the fecal excretion of both radioactively labeled and unlabeled bile acids. In addition, aerobic and anaerobic cultures of upper small intestinal aspirates, the Schilling vitamin B12 absorption test, and fecal fat analysis were performed. All patients developed marked diarrhea and steatorrhea after JIB. The bile acid breath test was positive in all 11 patients after JIB. In 7 of the 11 patients, this test was already slightly positive before JIB. In every instance, however, the bile acid breath test became significantly more abnormal after the bypass operation. The fecal excretion of labeled bile acids increased significantly. However, the increase in the quantitative excretion of the bile acids did not reach statistical significance. The concentrations of bile acids in fecal water were considerably below the levels required to induce diarrhea. This was mainly the result of a low fecal pH and consequent low aqueous solubility. Jejunoileal bypass effected a major shift in fecal bile acids from the secondary bile acids, lithocholic acid and deoxycholic acid, to the respective primary compounds, chenodeoxycholic acid and cholic acid. There were no significant changes in the small bowel bacteriologic findings after JIB. In 5 out of the 9 patients in whom bacteriologic studies were performed, the cultures were positive before the operation. The Schilling vitamin B12 absorption test showed in all patients a significant drop in the 24-hour urinary 57Co excretion rate after JIB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1979

Bile acid sulfates. III. Synthesis of 7- and 12-monosulfates of bile acids and their conjugates using a sulfur trioxide-triethylamine complex.

The 7- and 12-monosulfates of chenodeoxycholic acid, deoxycholic acid, and cholic acid were prepared by sulfation of the protected bile acids with sulfur trioxide-triethylamine in pyridine overnight and were isolated by precipitation as the p-toluidinium salt after removing the protecting group(s). The taurine conjugates were obtained by conjugating the bile acid sulfates with taurine in hot dimethylformamide (DMF) in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). A new procedure of preparing glycine conjugated bile acid sulfates by direct conjugation of the bile acid sulfate triethylammonium salt with ethyl glycinate in boiling chloroform in the presence of EEDQ is also described. The advantage of these procedures over other procedures are their simplicity and their higher yields (tyically above 90%) The thin layer chromatographic mobilities of these sulfates are presented. The influence of side chain and hydroxyl group configurations on the properties of bile acid sulfates is briefly discussed.

Bile Acids and Salts↗

PubMed1993

Potentiation of butyrate-induced differentiation in human colon tumor cells by deoxycholate.

Human colon adenocarcinoma cells, treated with deoxycholate for 24 h prior to exposure to 1 mM butyrate, exhibited dose-dependent increases in the activities of three markers of colonic differentiation (alkaline phosphatase, lactase and CEA). Treatment with deoxycholate alone, for 24 h or longer, did not increase the secretion of CEA or the activities of either of the brush border-associated enzyme activities. Increases in differentiation markers were found to be bile acid-specific. Pretreatment with either dehydrocholic acid or cholic acid, even at cytotoxic concentrations, led to no significant butyrate-induced increases in brush-border associated hydrolase activities. The addition of a bacterial superoxide dismutase decreased the short-term cytotoxicity of deoxycholate and increased the maturation-potentiating effects of the bile acid in HCT-116 DO cells. The results of these studies demonstrate that bile acids, which are commonly thought to have tumor promoting activities in vivo, may also have physiological effects which serve to limit carcinogenic processes in the human colon by potentiating tumor cell differentiation.

Adenocarcinoma↗

PubMed1993

Lithocholic acid-sensitive mutant cells isolated from Chinese hamster ovary cells are cross-sensitive to cytoskeleton-disturbing agents.

The lithocholic acid-sensitive mutant cells were isolated from CHO-9 cells mutagenized with ethylmethane sulfonate, through clonal selection on 96-well dishes. The isolated mutant cells (LSJ-11) were 3-fold more sensitive than controls in the survival to lithocholic acid and were also sensitive to other bile acids such as deoxycholic acid and cholic acid. As a preliminary characterization, it was found that the mutant cells were also sensitive to cytoskeleton-disturbing agents such as colchicine, colcemide, taxol and cytochalasin B. This is the first observation that a bile acid-sensitive mutant was isolated and was partially characterized.

Animals↗

PubMed1987

Determination of some hydroxycholesterols in human serum samples.

The simultaneous determination of some hydroxycholesterols in human serum samples is described. The procedure is based on hydrolysis and extraction of these compounds in serum samples, followed by removal of especially cholesterol (making use of reversed-phase high-performance liquid chromatography) and derivatization of the purified compounds to their trimethylsilyl ethers and subsequent gas chromatography using flame ionization detection. Serum levels of 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol and 26-hydroxycholesterol were determined in several groups of patients: normals, untreated patients suffering from cerebrotendinous xanthomatosis, patients suffering from cerebrotendinous xanthomatosis and treated with either chenodeoxycholic acid or cholic acid in an effective dose, patients suffering from cerebro-hepato-renal syndrome, patients suffering from hypercholesterolemia and treated with cholestyramine for prolonged periods and one patient presumed to be suffering from an inborn error of metabolism in bile acid synthesis. It can be concluded that the 7 alpha-hydroxycholesterol concentration in serum is a good parameter for establishing disorders involving the metabolic conversion of 7 alpha-hydroxycholesterol towards bile acids. In addition, 26-hydroxycholesterol levels in patients suffering from cerebrotendinous xanthomatosis are beyond detectable limits, even during treatment with bile acids in an effective dose, whereas in all other conditions this compound is substantially present.

Chromatography, Gas↗

PubMed2004

Determination of underivatised sterols and bile acid trimethyl silyl ether methyl esters by gas chromatography-mass spectrometry-single ion monitoring in faeces.

A method for quantification of total faecal sterols and bile acids (BAs) in human stool by using gas chromatography-mass spectrometry-single ion monitoring (GC-MS-SIM) is described. Cholesterol, coprostanol, coprostanone, cholestanol, iso-lithocholic acid (iso-LCA), lithocholic acid (LCA), iso-deoxycholic acid (iso-DCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), cholic acid (CA), and 12-oxo-deoxycholic acid (12-oxo-DCA) in faeces of 86 healthy subjects were determined. The sample preparation for sterol analysis requires hydrolysis and liquid extraction from matrix, but no derivatisation. The GC-flame ionisation detection (FID) and total ion current (TIC) in GC-MS were not sufficient for sterol and BA determination, whereas selectivity and specificity of the GC-MS-SIM ensured the analysis of sterols and BAs in faeces.

Bile Acids and Salts↗

PubMed2006

ORF18-disrupted mutant of Comamonas testosteroni TA441 accumulates significant amounts of 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid and its derivatives after incubation with steroids.

In a steroid degradation gene cluster of Comamonas testosteroni TA441 consisting of ORF18, 17 and tesIHA2A1DEFG, ORF18 was implicated in encoding a CoA-transferase by database searches, but the matching substrate was not clear. In this study, ORF18 was shown to be necessary for conversion of 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid, a product of hydrolysis of 4,5-9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-dien-4-oic acid in steroid degradation by TA441. The ORF18-disrupted mutant accumulates 7-hydroxy-9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid and 7,12-dihydroxy-9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid when incubated with chenodeoxycholic acid and cholic acid, respectively.

Chromatography, High Pressure Liquid↗

PubMed2000

Mixed oxo-hydroxy bile acids as actual or potential impurities in ursodeoxycholic acid preparation: a 1H and 13C NMR study.

Some distinctive unprecedented 1H NMR signals and the complete 13C NMR resonances are assigned for the entire set of mixed oxo-hydroxy bile acid isomers, obtained by selective oxidation of the hydroxy groups at positions (3,7), (3,12) and (3,7,12) of chenodesoxycholic acid, desoxycholic acid and cholic acid, respectively. Partially or totally oxidized products are the major actual or potential impurities formed during the preparation of the pharmaceutically active ursodeoxycholic and chenodeoxycholic acids.

Bile Acids and Salts↗

PubMed1987

Studies on steroids. CCXXVIII Trace analysis of bile acids by gas chromatography-mass spectrometry with negative ion chemical ionization detection.

A suitable derivatization method for the trace analysis of bile acids by gas chromatography (GC) in combination with negative ion chemical ionization (NICI) mass spectrometry is described. Of various derivatives for the carboxyl group, the pentafluorobenzyl (PFB) ester provided the highest value of the ratio of the negative to the positive ion current. A characteristic carboxylate anion [M - 181]- was produced as the most abundant ion by the loss of the PFB group in NICI. The PFB esters were further derivatized to the dimethylethylsilyl (DMES) ethers, whereby lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid and cholic acid were distinctly separated by GC on a cross-linked methyl silicone fused-silica capillary column. The detection limit for the PFB-DMES derivatives of dihydroxylated bile acids was 2 fg when the fragment ion was monitored at m/z 563 in the NICI mode using isobutane as a reagent gas.

Bile Acids and Salts↗

PubMed1996

Synthesis of 3 alpha- and 3 beta-dimers from selected bile acids.

New dimers of bile acids have been synthesized by linking the hydroxyl groups on C3 of the steroid skeleton with a spacer via the formation of ester or ether bonds. 3 alpha-Dimers of lithocholic acid and cholic acid were prepared by forming ester linkages between the C3 hydroxyl group and dicarboxylic acids of different lengths, i.e., suberoyl chloride (eight carbons) and sebacoyl chloride (ten carbons). These dimers were obtained in three steps with an overall yield of about 70%. Regioselective hydrolysis of the methyl ester protecting groups on the bile acids was carried out successfully under mild alkaline conditions (aqueous lithium hydroxide with tetrahydrofuran). A 3 beta-dimer of lithocholic acid has also been synthesized by linking the C3 positions of two bile acids with diethylene glycol by the formation of ether linkages. The carboxylic acid groups of the bile acid dimer can be liberated by the removal of the methyl ester protecting groups.

Bile Acids and Salts↗

PubMedDate not supplied

Ion conductors derived from biogenic amines, bile acids, and amino acids.

A family of conjugates has been synthesized from spermine, putrescine, lysine, gamma-aminobutyric acid, sarcosine, cholic acid, glycocholic acid, 3alpha,7alpha-dihydroxycholic acid, and 3alpha,12alpha-dihydroxycholic acid, based on a design principle previously reported (Bandyopadhyay, P., Janout, V., Zhang, L., Regen, S. L. (2001) J. Am. Chem. Soc. 123, 7691). Each of these conjugates was found to exhibit significant activity in promoting the transport of Na(+) across liposomal membranes derived from 1,2-dimyristoleoyl-sn-glycero-3-phosphocholine, and also from 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine. In all cases, plots of pseudo first-order rate constants, k(obsd) vs (mol % of ion conductor)(2) were found to be linear, indicating that transport-active dimers are involved and that only a small fraction of the conjugates are in an aggregated form. An operational comparison that has been made within this series of conjugates indicates that Na(+) transport activity and membrane selectivity have a moderate dependency on the composition and the structure of the ion conductor.

Amino Acids↗

PubMed2002

Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor.

Inappropriate activation of the mineralocorticoid receptor (MR) results in renal sodium retention and potassium loss in patients with liver cirrhosis. Recent evidence suggested that this MR activation is, at least in part, a result of bile acid-dependent reduction in 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) activity, an enzyme preventing cortisol-dependent activation of MR by converting cortisol to cortisone. Here, we investigated the molecular mechanisms underlying bile acid-mediated MR activation. Analysis of urinary bile acids from 12 patients with biliary obstruction revealed highly elevated concentrations of chenodeoxycholic acid (CDCA), cholic acid (CA), and deoxycholic acid (DCA), with average concentrations of 50-80 microm. Although CDCA and DCA both mediated nuclear translocation of MR in the absence of 11 beta HSD2 and steroids in transiently expressing HEK-293 cells, the transcriptional activity of MR was not stimulated. In contrast, CDCA and DCA both inhibited 11 beta HSD2 with IC(50) values of 22 and 38 microm, respectively and caused cortisol-dependent nuclear translocation and increased transcriptional activity of MR. LCA, the bile acid that most efficiently inhibited 11 beta HSD2, was present at very low concentrations in cholestatic patients, whereas the weak inhibitor CA did not cause MR activation. In conclusion, these findings indicate that CDCA, and to a lesser extent DCA, by inhibiting 11 beta HSD2, mediate cortisol-dependent nuclear translocation and transcriptional activation of MR and are responsible at least for a part of the sodium retention and potassium excretion observed in patients with biliary obstruction.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed1981

Effects of cholesterol feeding on the bile acids of male and female germ-free rats.

The effect of cholesterol feeding on the intestinal bile acids was studied in male and female germ-free rats. The bile acid pattern of the male animals was not altered considerably by cholesterol supplementation. Bile acids belonging to the chenodeoxycholic acid pathway slightly increased whereas cholic acid decreased. beta-Muricholic acid remained the predominant bile acid in male rats. On the other hand, cholesterol feeding to female germ-free rats substantially changed the intestinal bile acid composition. The concentration of cholic acid fell to one third and that of beta-muricholic acid decreased by about half. On the contrary, the relative amounts of chenodeoxycholic acid, allochenodeoxycholic acid and alpha-muricholic acid increased several times. The most striking sex-linked effect of cholesterol feeding was the occurrence in female rats of a bile acid tentatively identified as 3 alpha, 7 beta-dihydroxy-6-oxo-5 beta-cholan-24-oic acid. This bile acid accounted for 16.0% and 26.6% of the total bile acids in the small intestine and in the cecum plus large intestine, respectively. Cholesterol feeding also influenced the sulfation of bile acids in female germ-free rats. In the small intestine the sulfated fraction increased from 1.1% to 2.8% and in cecum plus large intestine from 23.0% to 30.8%. Allochenodeoxycholic acid was the predominant bile acid in the sulfate fraction. The total amount of bile acids in cecum plus large intestine increased from 72.0 to 225.0 mg/kg body weight in male rats and from 64.8 to 231.3 mg/kg body weight in female animals.

Animals↗

PubMed1990

Comparative sequential changes in serum and biliary levels of bile acid components after a single dose of D-galactosamine or partial hepatectomy in the rat.

In order to characterize changes in bile acid profile during liver cell damage and regeneration, levels of bile acids in serum and bile were determined by high performance liquid chromatography (HPLC) in F344 rats treated with a single dose of D-galactosamine (galactosamine, 300 mg/kg, i.p.) or subjected to two-thirds partial hepatectomy (PH). In the serum, galactosamine caused elevation of conjugated bile acids such as taurocholic acid (TCA) and tauro-beta-muricholic acid (T beta MCA) at the 24 and 48-h time points, whereas unconjugated bile acids including cholic acid (CA) at 24 h and hyodeoxycholic acid (HDCA) at 48 h were increased after PH. In the bile, elevation of TCA showed most remarkable elevation at the 24-h time point in the galactosamine-treated group. All components of biliary bile acids showed rapid decreases from 24 to 48 h. The results demonstrated that while liver tissue damaged by galactosamine is able to conjugate bile acids it allows leakage into the blood stream. In contrast, the results for rats subjected to PH indicated that liver cells during DNA synthesis are not capable of conjugating all free bile acids with taurine although a similar leakage occurs. It is concluded that obvious elevation of serum TCA or CA and biliary T beta MCA could be a useful indicator of hepatocellular proliferation.

Animals↗