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PubMed1995

Hepatobiliary transport of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors conjugated with bile acids.

To obtain prodrugs with affinity to liver parenchymal cells, the hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors HR 780 and lovastatin (syn. mevinolin) were conjugated with the bile acids cholic acid, taurocholic acid, and glycocholic acid. Hepatic uptake and biliary excretion of the coupled drugs were investigated and compared with the noncoupled drugs. Studies were performed with livers of normal Wistar rats, and TR-/GT- Wistar rats with deficient drug excretion. The experiments showed that the parent drug HR 780 was slowly excreted into bile. In contrast, the excretion of the bile acid-conjugated HR 780 derivatives S 3554 (conjugated with cholate), S 3898 (conjugated with glycocholate), and S 4193 (conjugated with taurocholate) was rapid and very efficient in both groups of rat strains. The bile acid-conjugated HMG-CoA reductase inhibitors showed a 10 to 20 times higher affinity for the uptake systems of bile acids than the noncoupled parent drug compounds, and even higher affinities than the bile acids themselves. The cholate conjugate of HR 780 (compound S 3554) was shown to be a noncompetitive inhibitor of taurocholate uptake and a competitive inhibitor of sodium-independent cholate uptake (Ki = 1 mumol/L). Uptake of radiolabeled S 3554 into isolated rat hepatocytes was observed to be rapid, cell specific, saturable, energy dependent, and carrier mediated. However, the carrier for S 3554 uptake was found not to be the cloned Na(+)-dependent taurocholate cotransporting polypeptide Ntcp. Expression of this carrier cRNA in Xenopus laevis oocytes did not stimulate S 3554 uptake.

ATP-Binding Cassette Transporters↗

PubMed1995

Phenotypes of dnaA mutants of Escherichia coli sensitive to detergents and organic solvents.

We examined growth sensitivities of dnaA mutants of Escherichia coli to detergents (deoxycholic acid, cholic acid) and organic solvents (ethanol, glycerol). The dnaA602, dnaA604, dnaA5, and dnaA46 mutants with mutations in the putative ATP binding site of DnaA protein showed higher sensitivities to the detergents than did the wild-type strain. The dnaA508 and dnaA167 mutants with mutations in the N-terminal region of DnaA protein, however, showed higher sensitivities to organic solvents. The dnaA204 and dnaA205 mutants with a mutation in the C-terminal region of DnaA protein showed similar sensitivity as did the wild-type strain to reagents. Complementation analysis with a plasmid carrying the wild-type dnaA gene confirmed that dnaA mutations are responsible for these phenotypes that are sensitive to the reagents.

Bacterial Proteins↗

PubMed1989

Permeability of the rat biliary tree to ursodeoxycholic acid.

The permeability of the biliary epithelium to [14C]ursodeoxycholic acid (UDCA), a hypercholeretic bile acid, was compared to that of the 14C-labeled nonhypercholeretic bile acids cholic acid (CA), taurocholic acid (TCA), and tauroursodeoxycholic acid (TUDCA) by means of anterograde intrabiliary infusions and retrograde intrabiliary injections in the anesthetized rat. Anterograde intrabiliary infusions were performed by perfusing an isolated segment of common bile duct in vivo. After anterograde intrabiliary infusions, the fraction of unrecovered UDCA (that had presumably been absorbed from the biliary lumen) was 11.03 +/- 1.03 (SE)% (n = 6) of the administered dose. It was significantly higher than that of TUDCA (1.25 +/- 0.27%; n = 5; P less than 0.01), CA (2.62 +/- 0.43%; n = 4; P less than 0.01), and TCA (2.57 +/- 0.79%; n = 6; P less than 0.01). In separate experiments, bile was collected from the common bile duct and from the left hepatic duct. UDCA recovered from the left hepatic duct was found in the conjugated form, indicating that, after absorption in the common bile duct, it had been conjugated by the hepatocyte and secreted into bile. After retrograde intrabiliary injections of UDCA and CA, the cumulative percentages of recovered radioactivity were not significantly different (84.50 +/- 2.65 and 87.33 +/- 1.80%, respectively); however, peak recovery of UDCA was significantly delayed compared with that of CA. Moreover, UDCA was recovered mostly in the conjugated form, while CA was recovered mostly in the unconjugated form. These results suggest that, in the rat, UDCA is significantly more absorbed by the biliary tree than CA, TUDCA, and TCA. They support the hypothesis that UDCA undergoes a cholehepatic circulation.

Absorption↗

PubMed1989

Plasma clearance of bile acids in the rat: hepatic uptake under physiological conditions without countertransport.

Studies in rats by others indicated that sulfobromophthalein (BSP), bilirubin and indocyanine green are taken up by the liver and can be transported back to plasma against the prevailing concentration gradient (= countertransport). The present in vivo study was designed to determine whether the bile acids cholic acid and taurocholic acid under physiological conditions undergo appreciable countertransport as has been suggested by experiments in isolated hepatocytes. Experiments with BSP (controls) showed that injections of unlabeled BSP into rats five minutes after the administration of radiolabeled BSP was followed by a release of radioactivity into plasma (BSP-countertransport). In contrast bile acid countertransport could not be demonstrated, no matter whether it was tested 1, 5 or 8 minutes after the administration of radiolabeled cholic- or taurocholic acid.

Animals↗

PubMed1977

Effects of cholesterol feeding on synthesis and metabolism of cholesterol and bile acids in germfree rats.

The aim of the present investigation was to study the influence of cholesterol feeding on cholesterol synthesis and fecal excretion of bile acids in germfree rats. Four germfree rats were fed a basal diet containing 0.004% cholesterol and four germfree rats received the same diet supplemented with 0.4% cholesterol for 2 weeks. Cholesterol synthesis was studied by assaying the HMG CoA reductase activity in the liver microsomal fraction. Cholesterol feeding decreased the HMG CoA reductase activity from 28.5 +/- 6.6 (mean +/- SEM) to 9.1 +/- 0.7 pmol/mg protein per min. In another experiment four germfree rats received the basal diet and four germfree rats the cholesterol-enriched diet. After 6 weeks feces were collected in two 4-day pools for analysis of bile acids. The main fecal bile acids were cholic acid and beta-muricholic acid (a metabolite of chenodeoxycholic acid), comprising more than 95% of total bile acids. Cholic acid was increased from 3.9 +/- 0.2 to 9.9 +/- 1.2 mg/kg body weight per day and beta-muricholic acid from 6.6 +/- 0.5 to 21.8 +/- 3.1 mg/kg body weight per day. The percentage of cholic acid decreased from 37.1 +/- 1.1 to 31.2 +/- 1.0%. In conclusion, germfree rats like conventional rats have the ability to compensate for an increased input of dietary cholesterol by inhibition of cholesterol synthesis and stimulation of bile acid synthesis. The synthesis of chenodeoxycholic acid (implied from the fecal excretion of beta-muricholic acid) is stimulated to a greater extent than that of cholic acid.

Animals↗

PubMed2004

Role of farnesoid X receptor in the enhancement of canalicular bile acid output and excretion of unconjugated bile acids: a mechanism for protection against cholic acid-induced liver toxicity.

Mice lacking the farnesoid X receptor (FXR) involved in the maintenance of hepatic bile acid levels are highly sensitive to cholic acid-induced liver toxicity. Serum aspartate aminotransferase (AST) activity was elevated 15.7-fold after feeding a 0.25% cholic acid diet, whereas only slight increases in serum AST (1.7- and 2.5-fold) were observed in wild-type mice fed 0.25 and 1% cholic acid diet, respectively. Bile salt export pump mRNA and protein levels were increased in wild-type mice fed 1% cholic acid diet (2.1- and 3.0-fold) but were decreased in FXR-null mice fed 0.25% cholic acid diet. The bile acid output rate was 2.0- and 3.7-fold higher after feeding of 0.25 and 1.0% cholic acid diet in wild-type mice, respectively. On the other hand, no significant increase in bile acid output rate was observed in FXR-null mice fed 0.25% cholic acid diet in contrast to a significant decrease observed in mice fed a 1.0% cholic acid diet in spite of the markedly higher levels of hepatic tauro-conjugated bile acids. Unconjugated cholic acid was not detected in the bile of wild-type mice fed a control diet, but it was readily detected in wild-type mice fed 1% cholic acid diet. The ratio of biliary unconjugated cholic acid to total cholic acid (unconjugated cholic acid and tauro-conjugated cholic acid) reached 30% under conditions of hepatic taurine depletion. These results suggest that the cholic acid-induced enhancement of canalicular bile acid output rates and excretion of unconjugated bile acids are involved in adaptive responses for prevention of cholic acid-induced toxicity.

Adenosine Triphosphate↗

PubMed1992

Aqueous solubility and acidity constants of cholic, deoxycholic, chenodeoxycholic, and ursodeoxycholic acids.

Cholic acid, deoxycholic acid, chenodeoxycholic acid, and ursodeoxycholic acid were purified by a foam fractionation method. Using thermogravimetric analysis, the attached water molecule was found to be completely removed from solids of the latter three at 100 degrees C, while cholic acid still had one water molecule of crystallization per two cholic acid molecules at that temperature. The acidity constants of the acids were accurately determined from aqueous solubility measurements at different pH values and at 15, 25, 35, and 45 degrees C. The enthalpy change of dissolution from temperature dependence of solubility as undissociated acid monomer was much less than those of common ionic surfactants. This results from a smaller entropy increase on dissolution due to the hardly flexible hydrophobic structure of these bile acids.

Calibration↗

PubMed1985

Evidence for distinct precursor pools for biliary cholesterol and primary bile acids in cebus and cynomolgus monkeys.

The abnormal metabolism and distribution of plasma lipoproteins have been associated with atherosclerosis and gallstones. To better understand the process of cholesterol excretion, a study was designed to determine whether the contribution of lipoprotein free 14C-cholesterol (as LDL or HDL) to biliary cholesterol or primary bile acids differs in two species of nonhuman primates, cebus and cynomolgus monkeys, having opposite plasma LDL/HDL ratios. Since amino acid conjugation might influence bile acid synthesis or secretion, the taurine and glycine conjugates of newly synthesized primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), were measured in the species capable of conjugating with taurine or glycine (cynomolgus). After total bile acid pool washout, monkeys were infused with human LDL or HDL labeled with free 14C-cholesterol, and the specific activities (SA) of biliary cholesterol and primary bile acid conjugates were determined. In both species, regardless of the lipoprotein infused, the SA of biliary cholesterol and CA were greater than those for total bile acids and CDCA, respectively. In cynomolgus, the SA of glycine conjugates was higher for CA than CDCA, while the SA of taurine conjugates was greater for CDCA than CA. Under these conditions, (i) infused lipoprotein free cholesterol (as either LDL or HDL) contributed more to biliary cholesterol than to bile acids and more to CA than to CDCA; (ii) glycine conjugated preferentially with CA rather than CDCA, while taurine was the preferred conjugate for CDCA.

Animals↗

PubMed1989

[Determination of bile acids in bear gall drainage by thin layer chromatographic scanning].

A method for the quantitative determination of three main bile acids, cholic acid (CA), ursodesoxycholic acid (UDCA) and chenodesoxycholic acid (CDCA), in bear gall, drainage from bear gall and bear gallstone is described. Experimental conditions: TLC Scanner CS-910, fluorescence scanning, lambda ex 470 nm and lambda em 550 nm for CA; lambda ex 380 nm and lambda em 450 nm for UDCA and CDCA. The results showed that the contents of UDCA and CDCA in bear gall drainage were higher than those in bear gall. The method is simple, rapid and sensitive. The reproducibility is good. The average recovery is 98.4%, CV is 1.4%.

Animals↗

PubMed1978

Chenotherapy for gallstone dissolution. II. Induced changes in bile composition and gallstone response.

Changes in bile saturation and biliary bile acid composition in patients with gallstones who received chenodeoxycholic ("chenic") acid, cholic acid, or placebo were measured. Chenodeoxycholic induced bile desaturation; this effect was attributable solely to a decrease in the proportion of cholesterol. By gas chromatography, chenodeoxycholic acid increased substantially in the biliary bile acids of patients receiving it, and by mass spectrometry, no unusual bile acids were detected in appreciable amounts. Changes in bile saturation and biliary bile acid composition were then related to chenodeoxycholic acid dosage, and all of these variables were, in turn, related to gallstone response. In general, patients whose gallstones dissolved ingested a higher dose of chenodeoxycholic acid or had bile that contained a higher proportion of this acid and it was more unsaturated, but there were many exceptions, casting doubt on the value of a single analysis of fasting-state bile for predicting gallstone dissolutions. The major factor influencing response, provided dosage is adequate, appears to be gallstone type. Nonetheless, the proportion of chenodeoxycholic acid in biliary bile acids can probably be used to infer patient compliance.

Bile↗

PubMed2006

LC/ESI-tandem mass spectrometric determination of bile acid 3-sulfates in human urine 3beta-Sulfooxy-12alpha-hydroxy-5beta-cholanoic acid is an abundant nonamidated sulfate.

We developed a highly sensitive and quantitative method to detect bile acid 3-sulfates in human urine employing liquid chromatography/electrospray ionization-tandem mass spectrometry. This method allows simultaneous analysis of bile acid 3-sulfates, including nonamidated, glycine-, and taurine-conjugated bile acids, cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), ursodeoxycholic acid (UDCA), and lithocholic acid (LCA), using selected reaction monitoring (SRM) analysis. The method was applied to analyze bile acid 3-sulfates in human urine from healthy volunteers. The results indicated an unknown compound with the nonamidated common bile acid 3-sulfates on the chromatogram obtained by the selected reaction monitoring analysis. By comparison of the retention behavior and MS/MS spectrum of the unknown peak with the authentic specimen, the unknown compound was identified as 3beta,12alpha-dihydroxy-5beta-cholanoic acid 3-sulfate.

Adult↗

PubMed1979

The effect of cholestyramine on bile acid kinetics in healthy controls.

Serum lipids and the kinetics of the two primary bile acids, cholic acid (C) and chenodeoxycholic acid (CD), were studied in six normolipidaemic subjects before and during treatment with cholestyramine (12 g/day). After therapy, total serum and low-density lipoprotein cholesterol decreased by about 15%. These changes were accompanied by significant increases in the pool size, synthesis, and fractional turnover rate (FTR) of C and in the synthesis and FTR of CD. In spite of the enhanced formation of CD, the CD pool size decreased in all subjects, on average by more than 50%. The combined pool size of C and CD remained constant, but the mean total bile acid formation increased by a factor of 2.9. It is suggested that the different responses of C and CD, with an augmented contribution of C to the total amounts of bile acid produced, reflect an enhanced hepatic cholesterogenesis and, possibly, that C and CD to some extent originate from different cholesterol precursor pools.

Adult↗

PubMed1980

Serum bile acid concentrations in the course of benign recurrent intrahepatic cholestasis.

The patient reported here represents the classic features of the syndrome of benign recurrent intrahepatic cholestasis (BRIC). She had conjugated hyperbilirubinaemia during the neonatal period and early infancy. The concentrations of serum primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA) were determined by radioimmunoassay and were continuously extremely raised during the icteric, recovery, and also the anicteric phases of the disease. The ratio of CA to CDCA was always within the normal range. The secondary serum bile acid, deoxycholic acid (DCA), was only slightly raised. The oral cholate tolerance test was abnormal in the patient during the anicteric phase. These observations support the suggestion that a disturbance of the hepatocellular bile acid transport may be the primary defect in BRIC.

Bile Acids and Salts↗

PubMed1981

Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching.

Two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), and one secondary bile acid, deoxycholic acid (DCA), were measured by radioimmunoassay in pregnancy serum from 30 healthy women, 49 women with itching and 45 with intrahepatic cholestasis of pregnancy. All subjects were studied serially from between 16 and 20 weeks gestation until 35-60 days post partum. In healthy pregnant women, serum CA and DCA levels did not change significantly at any time. The mean CDCA level rose significantly towards term. In women with intrahepatic cholestasis, serum levels of CA and CDC were increased ten- and five-fold, respectively, at the time of appearance of clinical symptoms and the CA/CDCA ratio rose from 1/1 to 2/1; there was also a moderate increase in the serum concentration of DCA. In 4 of 8 women studied prospectively an increase in serum bile acid levels preceded the appearance of symptoms or other laboratory evidence of intrahepatic cholestasis. Nine of the women with itching with normal routine liver function test results had increases in serum CA and CDCA concentrations suggesting mild cholestasis.

Bile Acids and Salts↗

PubMed2000

The human liver-specific homolog of very long-chain acyl-CoA synthetase is cholate:CoA ligase.

Unconjugated bile acids must be activated to their CoA thioesters before conjugation to taurine or glycine can occur. A human homolog of very long-chain acyl-CoA synthetase, hVLCS-H2, has two requisite properties of a bile acid:CoA ligase, liver specificity and an endoplasmic reticulum subcellular localization. We investigated the ability of this enzyme to activate the primary bile acid, cholic acid, to its CoA derivative. When expressed in COS-1 cells, hVLCS-H2 exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both non-isotopic and radioactive assays. Other long- and very long-chain acyl-CoA synthetases were incapable of activating cholate. Endogenous choloyl-CoA synthetase activity was also detected in liver-derived HepG2 cells but not in kidney-derived COS-1 cells. Our results are consistent with a role for hVLCS-H2 in the re-activation and re-conjugation of bile acids entering liver from the enterohepatic circulation rather than in de novo bile acid synthesis.

Amino Acid Sequence↗

PubMed2001

Effect of bile acids on the uptake of irinotecan and its active metabolite, SN-38, by intestinal cells.

The intestinal transport of irinotecan (CPT-11) and its active metabolite, SN-38, has been previously reported (K. Kobayashi et al., Int. J. Cancer, 83 (1999) 491-496). In the present study, the effect of the two major primary bile acids, cholic acid (CA) and taurocholic acid (TCA), on the uptake of CPT-11 and SN-38 by hamster intestinal epithelial cells was investigated. These two bile acids at concentrations up to 200 microM did not directly alter the cellular uptake of CPT-11 and SN-38. However, under physiologically acidic intestinal pH conditions, micelle formation induced by 20 mM TCA significantly reduced the cellular uptake of CPT-11 and SN-38 by 60% and 80%, respectively.

Animals↗

PubMed2005

Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells.

BACKGROUND: Secondary bile acids such as deoxycholic acid (DCA) are known to promote colorectal cancer (CRC). Increasing evidence suggests that DCA-induced signaling is mediated by activation of the epidermal growth factor receptor (EGFR). We have shown that activation of the EGFR induces up-regulation of cyclooxygenase 2, basolateral release of prostaglandins (PGs), and mitogenesis in a polarizing human colon cancer cell line, HCA-7. The purpose of this study was to determine the mechanism by which DCA activates EGFR in human polarizing CRC cell lines HCA-7 and HCT-8. METHODS: A primary, non-tumor-promoting bile acid (cholic acid [CA]) and a secondary, tumor-promoting bile acid, DCA, were added to the apical and basolateral compartment of polarized HCA-7 and HCT-8 cells. These cells were pretreated with monoclonal antibody 528, a monoclonal antibody that inhibits ligand binding to EGFR, or with WAY-022, a selective inhibitor of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease-17 (TACE/ADAM-17), which cleaves amphiregulin (AR) to its mature, soluble form from the basolateral cell membrane. AR levels were measured in the apical and basolateral medium and cell lysates by radioimmunoassay. PGs were measured in the apical and basolateral medium by gas chromatography/mass spectrometry. RESULTS: Basolateral delivery of DCA, but not CA, preferentially stimulated release of AR into the basolateral medium compared with cell lysates of polarized HCA-7 and HCT-8 cells. Basolateral delivery of DCA resulted in increased basolateral PGE2 levels (P < .05), and this effect was attenuated by pretreatment with monoclonal antibody 528 (P < .05). Inhibiting cell surface cleavage of AR with WAY-022 before DCA treatment reduced AR (P < .05) and PGE2 (P < .05) levels in the basolateral medium. CONCLUSION: DCA, but not CA, results in compartment-specific, ligand-dependent activation of EGFR and subsequent increased basolateral PGE2 levels. The mechanism of DCA-induced EGFR activation is ligand-dependent and is controlled, at least in part, at the level of AR release from the basolateral cell membrane.

Amphiregulin↗

PubMed1986

Oxidoreduction of different hydroxyl groups in bile acids during their enterohepatic circulation in man.

The extent of oxidoreduction of the 3 alpha-, 7 alpha- and 12 alpha-hydroxyl groups in bile acids during the enterohepatic circulation in man was studied with the use of [3 beta-3H]-labeled deoxycholic acid and cholic acid, [7 beta-3H]-labeled cholic acid, and [12 beta-3H]-labeled deoxycholic acid and cholic acid. Each [3H]-labeled bile acid was given per os to healthy volunteers, together with the corresponding [24-14C]-labeled bile acid. The rate of oxidoreduction was calculated from the decrease in the ratio between 3H and 14C in the respective bile acid isolated from duodenal contents collected at different time intervals after administration of the labeled bile acids. The mean fractional conversion rate was found to be 0.29 day-1 for the 3 alpha-hydroxyl group in deoxycholic acid (n = 2), 0.18 day-1 for the 12 alpha-hydroxyl group in deoxycholic acid (n = 6), 0.09 day-1 for the 3 alpha-hydroxyl group in cholic acid (n = 3), 0.05 day-1 for the 7 alpha-hydroxyl group in cholic acid (n = 2), and 0.03 day-1 for the 12 alpha-hydroxyl group in cholic acid (n = 2). The extent of oxidoreduction of the 12 alpha-hydroxyl group in [12 beta-3H]-labeled deoxycholic acid given to two patients operated with subtotal colectomy and ileostomy was markedly reduced (less than 20% of normal).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗