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At least 127 records · Page 7Linked to original sources
PubMed2002

Bile acid derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide as new carbonic anhydrase inhibitors: synthesis and investigation of inhibition effects.

Bile acid amides (cholan-24-amides) of 5-substituted 1,3,4-thiadiazole-2-sulfonamide have been prepared from lithocholic, deoxycholic, cholic and dehydrocholic acids. Besides, the alcohol functional groups on the cholane ring systems were protected with acetyl group. Amides of the protected cholanes of lithocholic and cholic acids were also synthesized. Later, inhibition effects of these compounds on human carbonic anhydrase isozymes (HCA-I and II) have been investigated in vitro. For the most active compounds, inhibition constants ranged from 66 to 190nM for HCA-II with I(50) (molarity of inhibitor producing a 50% inhibition of CA activity). In addition, in vivo studies were performed for the synthesized compounds in Sprague-Dawley rats. The compounds (11 and 18) showed especially significant inhibition efficacy (p<0.001).

Animals↗
PubMedDate not supplied

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

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

Animals↗
PubMed1976

Synthesis and pharmacological properties of a phthalide derivative containing methoxy groups.

4,6-Dimethoxy-5-hydroxyphthalide 2 was obtained on three routes: by selective demethylation of 4,5,6-trimethoxyphthalide and by the action of formaldehyde on either syringic acid or acetylsyringic acid. Pharmacological tests carried out on rats showed that the product significantly increased bile excretion, its activity being five times higher than those of dehydrocholic acid.

Animals↗
PubMed1994

32P-postlabeling of bile components: bulky adduct-like behavior in polyethyleneimine-cellulose thin layer chromatography.

The 32P-postlabeling assay has been used widely in carcinogen-DNA adduct analysis because of its sensitivity and reproducibility. Cloned T4 polynucleotide kinase (PNK), routinely used in this assay, phosphorylates the 5'-OH groups of adducted nucleotides in the presence of [gamma-32P]ATP. However, as an exception to this property, PNK has been reported to phosphorylate non-adducted carcinogen metabolites, such as tetrol derivatives of benzo[a]pyrene and chrysene. Also, PNK phosphorylates both 5'-OH and 3'-OH groups of safrole-adducted deoxydinucleoside monophosphates having an unmodified purine in the 3'-position. In the present study we show that T4 PNK catalyzed the transfer of [32P]phosphate from [gamma-32P]ATP to rat bile components or purified bile acids (derivatives of 3 alpha-hydroxy-5 beta-cholanic acid) in the absence of nucleic acids or nucleases. However, labeling of the bile acids appeared over 100,000-fold less efficient than labeling of 2'-deoxyadenosine-5'-monophosphate. There was no reaction in the absence of bile components or PNK. Dehydrocholic acid, which lacks hydroxyl groups, was resistant to phosphorylation. On polyethyleneimine-cellulose TLC maps, 32P-labeled rat bile extract gave an array of non-polar radioactive spots which resembled carcinogen-DNA adducts, while 32P-labeled purified bile acids each gave a single spot. These 32P-labeled products liberated 32Pi upon incubation with prostatic acid phosphatases. Two of the radioactive spots obtained from rat bile were identified as phosphorylated taurocholic and taurodeoxycholic acids by co-chromatography with 32P-labeled standards. These findings demonstrate for the first time that PNK is able to phosphorylate natural products other than nucleotides and further emphasize the need to rule out contamination with bile acids and possibly other bulky/hydrophobic alcohols when analyzing DNA samples by 32P-postlabeling.

Adenosine Triphosphate↗
PubMed1991

Precolumn fluorescence tagging reagent for carboxylic acids in high-performance liquid chromatography: 4-substituted-7-aminoalkylamino-2,1,3-benzoxadiazoles.

Four new 2,1,3-benzoxadiazole amine reagents having different functional groups at the 4- and 7-positions, [4-nitro-7-N-piperazino-2,1,3-benzoxadiazole (NBD-PZ), 4-(N,N-dimethylaminosulphonyl)-7-N-piperazino-2,1,3-benzoxad iazole (DBD-PZ), 4-(N,N-dimethylaminosulphonyl)-7-N-cadaverino-2,1,3-benzoxad iazole (DBD-CD) and ammonium 7-N-piperazino-2,1,3-benzoxadiazole-4-sulphonate (SBD-PZ)] were synthesized as fluorogenic tagging reagents for carboxylic acids in high-performance liquid chromatography. The reagents, except SBD-PZ, reacted with carboxylic acid at room temperature in the presence of activation agents to produce fluorescent adducts. The maximum wavelengths of arachidic acid tagged with DBD-PZ, DBD-CD and NBD-PZ were 569 nm (excitation, 440 nm), 561 nm (excitation, 437 nm) and 541 nm (excitation, 470 nm), respectively. Among various activation agents tested [diethyl phosphorocyanidate (DEPC), diphenyl phosphoroyl azide (DPPA), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-pyridine, 2.2'-dipyridyl disulphide-triphenylphosphine (Mukaiyama A) and 2-chloro-1-methylpyridinium iodide-triethylamine (Mukaiyama B)], DEPC and Mukaiyama A were more effective than the others. When the piperazino reagents (DBD-PZ and NBD-PZ) were used as the tagging reagents, the derivatization reaction in the presence of Mukaiyama A was faster than that in the presence of DEPC. Although the reaction in the presence of Mukaiyama A was completed after 30 min, an unknown peak derived from the activation agent appeared on the chromatograms. The fluorescence peak intensities were compared in the presence of DEPC. The order of the fluorescence peak areas obtained after reaction for 6 h in the presence of DEPC was DBD-PZ greater than DBD-CD greater than NBD-PZ. Thirteen saturated free fatty acids (FFAs) derivatized with DBD-PZ (or DBD-CD) and DEPC (or Mukaiyama A) in acetonitrile were separated completely by linear gradient elution on a reversed-phase ODS column. Eight drugs (ibuprofen, indomethacin, dinoprost, prostaglandin E1, dehydrocholic acid, ursodesoxycholic acid, hydrocartisone succinate and prednisolone succinate) were also tagged with DBD-PZ in the presence of DEPC and separated by isocratic elution. The detection limits (signal-to-noise ratio = 3) of FFAs tagged with DBD-PZ were in the range 3.2-4.7 fmol, whereas those of drugs were in the range 3.9-14 fmol.

Anti-Inflammatory Agents↗
PubMed1988

Regulation of biliary protein secretion in dogs.

The biliary secretion of protein in response to bile acids and other agents known to increase bile flow was examined in a chronic bile fistula dog model. Infusion of 25, 50, or 75 mumole/kg/hr sodium taurocholate after 3 hr of bile fistulization increased biliary protein output significantly by 52, 86, and 108% respectively compared to preinfusion values. A proportionate increase in biliary albumin output during taurocholate choleresis was demonstrated. Protein outputs during bile fistulization without taurocholate replacement were unchanged. The non-micelle-forming bile acid dehydrocholate markedly increased bile flow but did not change protein output. Similarly, the hormonal choleretics glucagon and secretin caused significant decreases in biliary protein concentration but no change in protein output. These data indicate a correlation between biliary protein secretion and bile acid-dependent bile flow. It is likely that regulation of certain proteins is dependent on the micelle-forming properties of bile acids.

Animals↗
PubMed1976

[Effect of some choleretics on the hepatic flow and its composition in man].

Four choleretics, selected at random from the German list of medical preparations, were tested with regards to their influence on hepatic bile production and bile composition. The investigations were performed on patients with a T-drainage in the ductus choledochus after bile duct revision. Bile was collected after fasting (90 min) and after administration of the drugs to be tested (3 hours). The choleretics were administered orally in a dosage two to five times more than the recommended one. Besides the bile volume bile acids, cholesterol, bilirubin, bicarbonate, potassium, sodium and calcium were determined. None of the parameters could be definitely influenced by these drugs. On the other hand a pronounced increase in the bile flow as well as the expected change in the other parameters could be observed after standardized secretion-stimulation which had been additionally carried out in half of the patients (dehydrocholic acid, i.v., taurocholic acid intraduodenally, secretin i.v., meals).

Adult↗
PubMed2002

Choleretic activity and biliary elimination of lipids and bile acids induced by an artichoke leaf extract in rats.

The therapeutic properties of artichoke (Cynara scolymus L.) preparations have been known since ancient times. The traditional use of artichoke leaf extract (ALE) in gastroenterology is mainly based upon its strong antidyspeptic actions which are mediated by its choleretic activity. The aim of this study was to investigate the effects of ALE on bile flow and the formation of bile compounds in anaesthetised Wistar rats after acute and repeated (twice a day for 7 consecutive days) oral administration. A significant increase in bile flow was observed after acute treatment with ALE as well as after repeated administration. The choleretic effects of ALE were similar to those of the reference compound dehydrocholic acid (DHCA). Total bile acids, cholesterol and phospholipid were determined by enzymatic assays. There was a strong ALE-induced increase in total bile acid concentration over the entire experiment. With the highest dose (400 mg/kg), a significant increase was obtained after single and repeated administration. The bile acids-increased effects of ALE were much more pronounced than those of reference (DHCA). No significant differences in cholesterol and phospholipid content could be found.

Administration, Oral↗
PubMed1988

Primary liver cell cultures grown on gas permeable membrane as source for the collection of primary bile.

Isolated rat hepatocytes maintained in primary culture on gas permeable membrane for 20 h form monolayers and establish at their cell borders a network of canaliculi (approximate diameter 3.5 micron). In the presence of the known choleretic bile acid dehydrocholate, dilation of canaliculi occurs. When nonfluorescent carboxyfluorescein diacetate ester is added to the culture medium, fluorescent carboxyfluorescein appears in the intracanalicular space. In the dilated state, fluid containing the fluorescent compound could be collected from the canaliculi by puncture with a micropipette. The intracanalicular space shows a negative electrical potential difference of 31 mV in reference to the bath solution and is 13.5 mV more positive with reference to recordings from the cytosol of cultured rat hepatocytes. Cultured rat hepatocytes grown on gas permeable membrane are energetically stable over 3 d. On Day 4, ATP levels increase markedly, whereas Na+-K+-ATPase activity declines. Ionic composition of hepatocytes, as measured by electronprobe element analysis on cryosection samples, does not change markedly during monolayer formation. With formation of bile canaliculi, the activity of alkaline phosphatase rapidly increases within 24 h and is stable for the next 3 d. Within that time the activity of gamma-glutamyltranspeptidase, however, increases steadily, reaching a 1.6-fold higher activity than freshly isolated hepatocytes. Bile acids appear in the culture supernatant after 1 d. When unconjugated [14C]cholic acid is added to the cultures the supernatant contains also [14C]tauro- and [14C]glycocholic acid, indicating the preservation of conjugation capacity in these cultures. Total bile acid concentrations in the supernatant increase from 5 to 26 microM on Day 4. The cultures do not secrete alpha-fetoprotein. Monolayer cultures of hepatocytes in the presence of choleretic bile acids seem to be a suitable model system to collect and to analyze the composition of primary bile. In conjunction with the electrical parameters, it is possible to describe directly properties of bile secretion at the canalicular pole of the intact hepatocyte.

Adenine Nucleotides↗
PubMed1996

Enzyme reactions in a multicompartment electrolyzer with isoelectrically trapped enzymes.

UNLABELLED: The possibility of performing bioconversions under an electric field is here reported. A system is described by which the enzyme is trapped by an isoelectric mechanism between two zwitterionic membranes having pI values encompassing the isoelectric point of the enzyme. The enzyme is loaded into a multicompartment electrolyzer and kept operating under an electric field, which will continuously harvest the reaction product. Since, under focusing conditions, all buffering ions will vacate the reaction chamber at steady state, the buffering ion is trapped into the enzyme chamber by using amphoteric buffers co-isoelectric with the enzyme. As an example of such "isoelectrically immobilized' reactor, the enzyme beta-hydroxysteroid dehydrogenase is blocked into an isoelectric trap delimited by a pI 8.0 and a pI 6.5 membranes. 100 mM histidine (pI 7.47) is co-immobilized by the same isoelectric mechanism into the enzyme chamber. The dehydrocholic acid substrate (3,7,12-trioxo-5 beta-cholanoic acid) and reduced co-factor (NADH) are continuously infused into the enzyme chamber and the product (3 beta-hydroxy-7,12-dioxo- 5 beta-cholanoic acid, a compound of pharmaceutical interest) and the oxidized co-factor (NAD+) collected, separately, into the two neighbouring chambers at the anodic side. ADVANTAGES: in a soluble form, the enzyme maintains the reaction kinetics of the free soluble form. Additionally, the reaction product and exhausted co-factor can be recovered by electrophoretic transport.

3-Hydroxysteroid Dehydrogenases↗
PubMed1989

Enzymatic synthesis of [4R-2H]NAD (P)H and [4S-2H]NAD(P)H and determination of the stereospecificity of 7 alpha- and 12 alpha hydroxysteroid dehydrogenase.

The stereospecifically labeled coenzymes [4R-2H]NADH, [4R-2H]NADPH and [4S-2H]NAD(P)H were synthesized enzymatically in high yield and high isotopic purity (greater than or equal to 95%) with 2HCOO2H/formate dehydrogenase, (CH3)2C2HOH/alchol dehydrogenase from Thermoanaerobium brockii and [1-2H]glucose/glucose dehydrogenase, respectively. This set of deuterated coenzymes was used to determine the stereospecificity of the previously unstudied 7 alpha-hydroxysteroid dehydrogenase from Escherichia coli (NAD-dependent) and 12 alpha-hydroxysteroid dehydrogenase from Clostridium group P (NADP-dependent). H-NMR and EI-MS of the nicotinamide moiety after enzymatic oxidation of deuterated NAD(P)H with dehydrocholic acid as substrate showed that both dehydrogenases are B-sterospecific.

Clostridium↗
PubMed1998

Evaluation and optimisation of separation buffers for the determination of corticosteroids with micellar electrokinetic capillary chromatography (MECC).

Separation buffers for the determination of the corticosteroids cortisone, hydrocortisone, prednisone and prednisolone with micellar electrokinetic chromatography were developed with respect to separation efficacy and the migration times, depending on the type and the concentration of the organic modifier acetonitrile as well as on the addition of gamma-cyclodextrin. The buffer containing 50 mM SDS and 16% (v/v) acetonitrile enables the rapid profiling of prednisolone together with cortisone and prednisone. Addition of gamma-cyclodextrin alters the elution sequence, but does not further enhance resolution of the corticosteroids. Baseline separation at long migration times for cortisone, hydrocortisone, prednisone and prednisolone is achieved with a buffer containing 50 mM each of SDS, dehydrocholic acid sodium salt and glycodeoxycholic acid sodium salt.

Acetonitriles↗
PubMed1986

Further studies on the inhibition of pepsin by bile salts.

A higher incidence of peptic ulceration has been reported in patients recovering from operations that divert bile from the duodenum. Previous studies have shown that hydroxylated bile salts inhibit the proteolytic activity of pepsin, an integral agent in the production of peptic ulcer. In this study, the pepsin inhibitory activity of 16 bile salts (6 unconjugated, 5 glycoconjugated, and 5 tauroconjugated bile salts), including bile salts with no hydroxyl groups, was tested in vitro. All bile salts inhibited pepsin proteolytic activity and the degree of pepsin inhibition increased in proportion to their concentrations. The range of maximal inhibition was 90-73% for unconjugated bile salts; 74-35% for glycoconjugated bile salts; and 71-46% for tauroconjugated bile salts. These findings support the need for clinical studies to evaluate administration of bile acids to bile-diverted patients.

Animals↗
PubMed1977

Cholic acid binding to isolated rat liver plasma membranes.

Cholic acid binding to isolated rat liver plasma membranes was studied using a centrifugal filtration technique which allowed independent determination of free and membrane-bound cholic acid. Binding of cholic acid was very rapid and reversible. Scatchard analysis revealed at least three binding sites with high, medium and low affinity. The high affinity binding a) displayed saturability and isotope replacement, b) was not present in rat liver mitochondria and red blood cell ghosts and c) was temperature dependent. This binding has a very low capacity with a dissociation constant in the physiological range of plasma cholic acid concentration and has an affinity for other common bile acids. Cholic acid binding to the high affinity binding site was not inhibited by estrone, beta-estradiol or cholesterol. These results would suggest that the high affinity binding site represents a specific binding site for cholic acid and may also be specific for other common bile acids. This binding was not dependent on Na and was inhibited by bromosulfophthalein. Cholic acid binding to the high affinity site has some features in common with cholic acid uptake by isolated rat hepatocytes, and this would suggest that the high affinity binding site could be the postulated carrier for hepatic uptake of cholic acid.

Animals↗
PubMed1987

[Cholagogic effect of trimethylglycine in normal animals of different ages and in experimental atherosclerosis].

Trimethylglycine at a dose of 1.5 g/kg was found to produce marked bile secretory effect in young and old rats. In rabbits with experimental atherosclerosis, trimethylglycine increased the content of biliary acids in the bile and normalized the indexes of lipid metabolism in the blood serum. Apparently, the effect on cholesterol transformation into biliary acids and its excretion with the bile is one of the mechanisms of anti-atherosclerotic action of trimethylglycine.

Aging↗