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PubMed1987

Lack of mutagenic activity of bile acids in bacterial fluctuation tests.

3 bile acids (cholic acid, chenodeoxycholic acid and deoxycholic acid) were assayed for mutagenicity in Salmonella typhimurium TA98 and TA100 in fluctuation tests in the absence of an external source of metabolic activation. At the doses tested, there were no dose-related statistically significant increases in mutagenicity compared with appropriate controls. These results do not support the claim (Watabe, J., and H. Bernstein (1985) Mutation Res., 158, 45-51) that these bile acids are mutagenic.

Bile Acids and Salts↗

PubMed1971

Bile salts of germ-free domestic fowl and pigs.

1. The bile of germ-free domestic fowl contains taurine conjugates of 3alpha,7alpha-dihydroxy-5beta-cholan-24-oic acid (chenodeoxycholic acid), 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid (cholic acid) and its 5alpha-epimer (allocholic acid): that of germ-free pigs contains glycine and taurine conjugates of chenodeoxycholic acid, 3alpha,6alpha-dihydroxy-5beta-cholan-24-oic acid (hyodeoxycholic acid), 3alpha,6alpha,7alpha-trihydroxy-5beta-cholan-24-oic acid (hyocholic acid) and (probably) cholic acid. Keto acids were not found. 2. Allocholic acid and hyodeoxycholic acid are thus proved to be primary bile acids in intact animals. 3. The evolutionary and biochemical implications of these findings are briefly considered.

Animals↗

PubMed1995

Long-term effects of cholecystectomy on bile acid metabolism.

Comparative studies between different patient groups have suggested that cholecystectomy enhances bacterial dehydroxylation of the primary bile acid cholic acid (CA) to the secondary bile acid deoxycholic acid (DCA). DCA may exert a cocarcinogenic effect on the colonic mucosa. In a short-term follow-up study on nine female patients we found no alterations of the CA or DCA pools after cholecystectomy. However, in the long term, cholecystectomy could promote changes of the intestinal bacterial flora and thereby lead to enhanced conversion of CA to DCA, causing an expansion of the DCA pool size and a reduction of the CA pool size. To test this hypothesis, pool sizes, fractional turnover rates (FTR), and synthesis or input rates of CA, chenodeoxycholic acid (CDCA) and DCA were determined in 12 female patients before and again 5 to 8 years after cholecystectomy. In the long term, pool size and synthesis rate of CA had not changed and DCA pool size had expanded by only 7.5% (not significant [NS]). DCA input increased by 32% (NS) but was balanced by an increase in FTR of 36%. Pool size (-17%) and synthesis rate (-5%) of CDCA were not significantly diminished. Overall, the sizes of the total bile acid pool (-6%, NS; 50 +/- 8 vs. 53 +/- 13 mumol/kg) and the pool fractions of CA (44.7 +/- 10.3% vs. 42.8 +/- 7.6%) and DCA (25.5 +/- 14.1% vs. 23.6 +/- 9.3%) remained similar. In conclusion, cholecystectomy causes no changes in bile acid pool composition and thus has no adverse effects on bile acid metabolism in the long term.

Adult↗

PubMed1987

Deficient cholesterol side chain oxidation in patients without peroxisomes (Zellweger syndrome): evidence for the involvement of peroxisomes in bile acid synthesis in man.

The absence of peroxisomes in patients with the cerebro-hepato-renal (Zellweger) syndrome is accompanied by a number of biochemical abnormalities including the accumulation of the bile acid intermediates di- and trihydroxycoprostanoic acid. In this paper we show that there is a marked deficiency in the oxidative side chain cleavage of cholesterol in liver from Zellweger patients. These findings not only provide an explanation for the low levels of the major naturally occurring bile acids, cholic acid and chenodeoxycholic acid and the accumulation of di- and trihydroxycoprostanoic acid in Zellweger patients, but also suggest that peroxisomes are essential in bile acid synthesis in man.

Bile Acids and Salts↗

PubMed1989

Effects of cholecystectomy on the kinetics of primary and secondary bile acids.

Removal of the gallbladder is thought to increase formation and pool size of secondary bile acids, mainly deoxycholic acid (DCA), by increased exposure of primary bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA]) to bacterial dehydroxylation in the intestine. We have tested this hypothesis by simultaneous determination of pool size and turnover of DCA, CA, and CDCA in nine women before and at various intervals after removal of a functioning gallbladder. An isotope dilution technique using marker bile acids labeled with stable isotopes (2H4-DCA, 13C-CA, 13C-CDCA) was used. After cholecystectomy, concentration and output of bile acids relative to bilirubin increased (P less than 0.02) in fasting duodenal bile and cholesterol saturation decreased by 27% (P less than 0.05) consistent with enhanced enterohepatic cycling of bile acids. Three months after removal of the gallbladder bile acid kinetics were in a new steady state: pool size and turnover of CDCA were unchanged. Synthesis of CA, the precursor of DCA, was diminished by 37% (P = 0.05), probably resulting from feedback inhibition by continuous transhepatic flux of bile acids. The fraction of CA transferred after 7 alpha-dehydroxylation to the DCA pool increased from 46 +/- 16 to 66 +/- 32% (P less than 0.05). However, this enhanced transfer did not lead to increased input or size of the DCA pool, because synthesis of the precursor CA had decreased.

Bile Acids and Salts↗

PubMed1994

Inhibition of rat liver microsomal bilirubin UDP-glucuronosyltransferase by ursodeoxycholic acid.

Ursodeoxycholic acid and its endogenous metabolite tauroursodeoxycholic acid inhibited in vitro the microsomal bilirubin UDP-glucuronosyltransferase from rat liver. The magnitude of the inhibition correlated well with the loss of integrity of microsomal vesicles, suggesting that bile salts needed to reach the lumen to exert their inhibitory effects. The endogenous bile acids cholic acid, chenodeoxycholic acid and deoxycholic acid also exhibited inhibitory effects on bilirubin glucuronidation in digitonin-disrupted microsomes. Ursodeoxycholic acid inhibitory capacity was similar to that of chenodeoxycholic acid and deoxycholic acid but greater than that of cholic acid, the major endogenous bile salt. Kinetic studies, performed in detergent-activated preparations, showed that the inhibitions produced by ursodeoxycholic and tauroursodeoxycholic acids were competitive toward both bilirubin and UDP-glucuronic acid. The estimated Ki(app) for both substrates did not differ statistically between ursodeoxycholic and tauroursodeoxycholic acids. Both bile salts were weak inhibitors toward bilirubin but rather strong inhibitors toward UDP-glucuronic acid.

Animals↗

PubMed1982

Serum bile acids during biphasic contraceptive treatment with ethinyl estradiol and norgestrel.

Twenty-nine women were treated with biphasic combined oral contraceptive pills containing ethinyl estradiol 0.05 mg and levonorgestrel 0.050-0.125 mg. Serum primary bile acids (cholic acid and chenodeoxycholic acid) and one secondary bile acid (deoxycholic acid) were measured by radioimmunoassay. The serum samples were collected before the treatment and at one, three and twelve months during the treatment. No significant changes were found in these bile acid levels during the treatment. The ratio of cholic/chenodeoxycholic acid did not change either. No pathological values were found in the conventional liver function tests although serum alanine aminotransferase activity was significantly increased after twelve months' treatment. It can therefore be concluded that the present contraceptive pill does not cause any liver dysfunction detectable by bile acid measurements of other "classical" liver function tests.

Adolescent↗

PubMed1985

Bile acid induction of 7 alpha- and 7 beta-hydroxysteroid dehydrogenases in Clostridium limosum.

When grown in the presence of bile acids, two strains of Clostridium limosum were found to contain significant amounts of NADP-dependent 7 alpha/7 beta-hydroxysteroid dehydrogenase and NAD-dependent 7 alpha-hydroxysteroid dehydrogenase which were active against conjugated and unconjugated bile acids. No measurable activity could be found when deoxycholic acid (3 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acid) was used as substrate. No 7 beta-hydroxysteroid dehydrogenase activity and only a trace of 7 alpha-hydroxysteroid dehydrogenase activity could be demonstrated when bile acid was deleted from the growth medium. If bile acid was added after the time of inoculation, the amounts of 7 alpha/7 beta-hydroxysteroid dehydrogenase were greatly reduced. Enzyme enhancement was blocked by addition of rifampicin. The 7 alpha/7 beta-hydroxysteroid dehydrogenase components had pH optima of approximately 10.5. Both the 7 alpha/7 beta-hydroxysteroid dehydrogenase activities were heat-labile, with the 7 beta-component being the more stable of the two. When ranked according to the level of enzymes induced, the order in increasing bile acid induction power on an equimolar scale (0.4 mM) was: 7-ketodeoxycholic acid, cholic acid, chenodeoxycholic acid, and deoxycholic acid. Both 7-ketolithocholic acid and ursodeoxycholic acid were ineffective as enzyme inducers. Optimal induction was achieved with high concentrations of cholic acid (5 mM) and a harvest time of 24 hr. Addition of ursodeoxycholic acid to medium containing optimal concentrations of deoxycholic acid suppressed enzyme induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Acids and Salts↗

PubMed1982

Lymphatic transport of bile acids in man.

The possibility of a lymphatic transport of bile acids in man was investigated. Four patients were studied 2-4 weeks after renal transplantation. As a part of the postoperative immunosuppressive treatment they all had a thoracic duct fistula for lymphatic drainage. After a standardized meal, lymph and peripheral blood samples were simultaneously collected at 30-minute intervals for 210 minutes. The bile acids, cholic acid, chenodeoxycholic acid, and deoxycholic acid were assayed by a gas-liquid chromatography-mass spectrometry method using deuterium-labeled internal standards. The concentration of cholic acid was about the same in lymph and serum. The concentrations of chenodeoxycholic and deoxycholic acids were 2-3 times higher in lymph than in serum, both in the fasting state and postprandially. These results are explained by a more efficient passive absorption of the less polar dihydroxy bile acids. The transport of bile acids in the lymph was calculated to be only about 0.2% of that in the portal vein.

Adult↗

PubMed1970

The synthesis of bile acids in perfused rat liver subjected to chronic biliary drainage.

1. Isolated rat liver was perfused with heparinized whole blood under physiological pressure resulting in the secretion of bile at about the rate observed in vivo. 2. The preparation remained metabolically active for 4h and was apparently normal in function and microscopic appearance. 3. When the perfusate plasma and liver cholesterol pool was labelled by the introduction of [2-(14)C]mevalonic acid the specific radioactivity of the perfusate cholesterol increased. The biliary acids (cholic acid and chenodeoxycholic acid) were labelled and had the same specific radioactivity. 4. Livers removed from rats immediately after, and 40h after, the start of total biliary drainage, were perfused; increased excretion rates of both cholic acid and chenodeoxycholic acid were found when the liver donors had been subjected to biliary drainage. 5. The incorporation of [2-(14)C]mevalonic acid or rat lipoprotein labelled with [(14)C]cholesterol into bile acids was studied. 6. A dissociation between the mass of bile acid excreted and the rate of incorporation of (14)C was found. This was attributed to the changing specific radioactivity of the cholesterol pool acting as the immediate bile acid precursor.

Animals↗

PubMed1985

Biliary lipid output and bile acid kinetics in cholesterol gallstone disease. Evidence for an increased hepatic secretion of cholesterol in Swedish patients.

Sweden has one of the highest incidences of gallstone disease in the Western world. It is therefore important to characterize the mechanisms responsible for the formation of cholesterol gallstones in this population. In the present study, we have determined the kinetics of the two primary bile acids, cholic acid and chenodeoxycholic acid, and the hepatic secretion rates of the biliary lipids in 21 normolipidemic, nonobese gallstone patients (13 with functioning and 8 with nonfunctioning gallbladder) and in 23 healthy controls. The cholesterol saturation of fasting gallbladder bile averaged 110% in the gallstone patients with functioning gallbladder and 82% in the controls. The pool sizes of cholic acid and chenodeoxycholic acid were reduced by about 40% in the two groups of gallstone patients, whereas the rates of synthesis were close to normal. The fractional catabolic rate of both bile acids was increased in both groups of gallstone patients. The gallstone patients with functioning gallbladder had an increased (about 50%) cholesterol secretion but normal bile acid and phospholipid secretion rates. In the gallstone patients with nonfunctioning gallbladder the secretion rates of biliary lipids were not significantly different from those of the controls. The ratio between cholesterol and bile acids was about 50% higher in the gallstone patients with functioning gallbladder than in the controls or in those with nonfunctioning gallbladder. The results indicate that the hepatic secretion of cholesterol is an important determinant for the development of saturated gallbladder bile in Swedish gallstone patients.

Adult↗

PubMed1990

Serum unconjugated primary and secondary bile acids in patients with cholangiocarcinoma and hepatocellular carcinoma.

Serum unconjugated primary bile acids (cholic acid, chenodeoxycholic acid), secondary bile acids (lithocholic acid, deoxycholic acid), conjugated primary bile acids (glycocholic acid, glycohenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid) and total bile acids were measured in 25 and 75 male patients with cholangiocarcinoma and hepatocellular carcinoma respectively. Twenty-one healthy male volunteers served as controls. Other biochemical parameters, i.e. bilirubin, transaminases, albumin, globulin and cholesterol were also studied. Conjugated bile acids and total bile acids were elevated in both patient groups when compared with those of controls. The presence of unconjugated primary bile acids and secondary bile acids was noted in the patient groups, whereas, they were not detectable in controls. The appearance of these serum bile acids may be useful as a marker for early diagnosis of cholangiocarcinoma and hepatocellular carcinoma in people at-risk such as those who have chronic infection with Opisthorchis viverrini. Differentiation between the two types of tumor may be possible by using other parameters such as alpha-fetoprotein or other tumor markers newly discovered. An increase of the trihydroxy bile acids: dihydroxy bile acids and glycine conjugated bile acids: taurine conjugated bile acids ratios was shown in the patient groups. The latter may be due to the proportion of the increase of taurine conjugates being greater than the increase of glycine conjugates. The other biochemical parameters were significantly elevated in the patient groups except for albumin which was significantly decreased. The sensitivity of the tests for cholic acid, chenodeoxycholic acid, alkaline phosphatase and gamma glutamyl transferase was high.

Adenoma, Bile Duct↗

PubMed1979

An easy procedure for determination of molar activity (or specific activity) of bile acids in bile.

An easy procedure is described for determination of the molar activity of the major bile acids, labelled with 14C, in bile. The procedure involves initial enzymatic hydrolysis, by which the amino acid moieties are removed from the glycine and taurine conjugated bile acids by means of choloylglycine hydrolase, followed by thin-layer chromatographic separation of the unconjugated bile acids, cholic acid, chenodeoxycholic acid, and deoxycholic acid. Then the bile acids are eluted from the individual silica gel spots concerned. Finally, determination of the radioactivity by liquid scintillation counting and of the amount of substance by an enzymatic method using 3 alpha-hydroxysteroid dehydrogenase is performed in the eluates. The method requires only a small volume of sample and allows of separate determination of the molar activity of cholic acid and chenodeoxycholic acid, labelled with the same isotope, in the same sample.

3-Hydroxysteroid Dehydrogenases↗

PubMed2005

1H and 13C NMR characterization and stereochemical assignments of bile acids in aqueous media.

The unconjugated bile acids cholic acid, deoxycholic acid, and chenodeoxycholic acid; their glycine and taurine conjugates glycocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid; and a taurine conjugated ursodeoxycholic acid, tauroursodeoxycholic acid, were characterized through 1H and 13C NMR in aqueous media under the physiological pH region (7.4 +/- 0.1). Assignments of 1H and 13C signals of all the bile acids were made using a combination of several one- and two-dimensional, homonuclear (1H-1H) and heteronuclear (1H-13C) correlations as well as spectral editing NMR methods. Stereochemical assignment of the five-membered ring of the bile acids is reported here for the first time. The complete characterization of various bile acids in aqueous media presented here may have implications in the study of the pathophysiology of biliary diseases through human biliary fluids using NMR spectroscopy.

Bile Acids and Salts↗

PubMed1996

Toxicity order of cholanic acids using an immobilised cell biosensor.

There is considerable published evidence of the use of cells of various species to evaluate the toxicity of numerous compounds, many of pharmaceutical interest. The coupling of cell colonies with a suitable transduction device has led to the development in recent years of toxicity biosensors based on the alteration of a process or a cell metabolic function by the toxic substance under examination. A biosensor based on immobilised yeast cells (Saccharomyces cerevisiae) has been developed recently in this department for the purpose of performing a rapid toxicity test in aqueous environmental matrices. This biosensor has now been used in the toxicity screening of a number of sodium salts of conjugated and free cholanic acids. The "toxicity degree" scale, which was found by placing in decreasing order the values of the slopes of the straight lines obtained by quantifying changes in the behaviour of the respirometric curve, plotted before and after incubation, using known concentrations of cholanic acid sodium salts, was: deoxycholic acid > chenodeoxycholic acid > ursodeoxycholic acid > cholic acid, for free cholanic acids; and glycodeoxycholic acid > glycochenodeoxycholic acid > glycocholic acid, for glycocholanic acids. These values are in good agreement with published toxicity data obtained in vitro. This sensor can thus be considered to provide a valid instrument for the preliminary evaluation of the toxicity of organic compounds or drugs.

Biosensing Techniques↗

PubMed2004

DNA hypomethylation induced by non-genotoxic carcinogens in mouse and rat colon.

The ability of non-genotoxic colon carcinogens to induce DNA hypomethylation was evaluated. Administering 0, 0.2 and 0.4 mg/kg of 5-aza-2'-deoxycytidine to female mice for 5 days resulted in a dose-related decrease in 5-methylcytosine in colon DNA. Rutin (3.0 mg/kg) and five bile acids (4.0 mg/kg) were administered in the diet to male F344 rats for 14 days. Rutin and four bile acids that promote colon cancer, deoxycholic acid, chenodeoxycholic acid, cholic acid and lithocholic acid caused DNA hypomethylation, while ursodeoxycholic acid that prevents colon cancer did not. Bromodichloromethane (BDCM) was administered to male F344 rats and B6C3F1 mice by gavage at 0, 50 and 100 mg/kg or in their drinking water at 0, 350 and 700 mg/l for up to 28 days. In rats, BDCM decreased DNA methylation, being more effective when administered by gavage, correlating to its greater carcinogenic potency by this route. In mice, BDCM did not decrease DNA methylation, corresponding to its lack of carcinogenic activity in the colon of this species. In summary, the ability of non-genotoxic colon carcinogens to cause DNA hypomethylation correlated with their carcinogenic activity in the colon.

Animals↗

PubMed1975

Hepatic bile acid transport: effect of conjugation and position of hydroxyl groups.

The hepatic transport of five bile acids was studied in the bile-fistula rat. Pairs of labeled bile acids were injected simultaneously into the portal vein as a sharp pulse and the secretion of radiolabel in bile was measured over the nex 15 min. Six bile acid pairs were tested, and it was found that both conjugation and the number and disposition of hydroxyl groups influenced hepatic transport. Taurocholic acid was transported most efficiently, followed in order by glycocholic acid, cholic acid, deoxycholic acid, and chenodeoxycholic acid. Sampling aortic blood immediately after portal vein injection of labeled bile acid pairs demonstrated differential rates of hepatic extraction. In every comparison, the bile acid that was more efficiently extracted by the liver had a faster overall transport rate. This suggests that the differing rates of biliary secretion are, at least in part, determined by the efficiency of hepatic uptake.

Animals↗

PubMed1979

Structure of bile acids associated with secretion in the rat cecum.

An isolated in vivo rat cecal loop technique was utilized to determine what structure of bile acids is required to stimulate net colonic secretion of water and sodium. A dose response curve for water and sodium movement was determined for deoxycholic acid (1-6 mM) and chenodeoxycholic acid (3-6 mM). Both of these bile acids were associated with significant secretion of water and sodium at 4 mM concentration. Therefore, this concentration was used for all test bile acids studied. Test solutions included the tri- and di-substituted bile acids: cholic acid, hyocholic acid, 3 alpha, 7 beta, 12 alpha-trihydroxycholanic acid, 3 alpha, 12 alpha-dihydroxy-7-ketocholanic acid, ursodeoxycholic acid, 3 alpha-hydroxy-7-ketocholanic acid, 7 alpha, 12 alpha-dihydroxycholanic acid, and hyodeoxycholic acid. Only three bile acids, deoxycholic acid, chenodeoxycholic acid, and 7 alpha, 12 alpha-dihydroxycholanic acid were associated with net secretion of water and sodium. Cecal histology after incubation with bile acids revealed mucosal alterations in those sacs in which secretion occurred, but not where absorption was noted. These data indicate that bile acid-associated water and sodium secretion in the rat cecum requires a specific bile acid structure with a definite spatial relationship of the hydroxyl groups. Secretion occurred only with two alpha-hydroxyl groups in either the 3, 7, or 12 positions.

Animals↗