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PubMed1991

Intravenous bilirubin infusion causes vacuolization of the cytoplasm of hepatocytes and canalicular cholestasis.

To examine whether intravenous bilirubin infusion causes cholestasis and impairs liver metabolism, bile secretion and ethanol clearance were measured in 34 anaesthetized pigs before and after intravenous infusion of 0.5 mumol kg-1 min-1 bilirubin for 4.5 hours. Bilirubin infusion increased plasma bilirubin to 556 +/- 76 mumol l-1 and hepatic tissue bilirubin to 3.5 +/- 1.3 mmol kg tissue weight-1. Bilirubin infusion depressed bilirubin secretion and net hepatic uptake of cholate and taurocholate, and caused a 86 +/- 6% reduction of cholate-induced bile secretion. Bilirubin caused formation of large cytoplasmic vacuoles in hepatocytes and dilatation of bile canaliculi. Ethanol clearance and secretin-dependent ductular bile secretion were unaffected by bilirubin. We conclude that intravenous infusion of unconjugated bilirubin causes accumulation of bilirubin in the liver, vacuolization of the hepatocyte cytoplasm and canalicular but not ductular cholestasis. The canalicular cholestasis is not due to impaired hepatic mitochondrial energy metabolism, but may be due to inhibition of a common pathway for lipid, bilirubin and bile salt secretion from hepatocytes.

Animals↗

PubMed1985

In-vitro enhancement of cholesterol dissolution by commonly used drugs.

A rotating disc apparatus was used to study the dissolution of cholesterol in sodium cholate solutions and ox bile. Drugs with structures that render them capable of lowering interfacial resistance were tested and shown to increase cholesterol dissolution rates in both systems. In sodium cholate solutions, loperamide (3 X 10(-4)M) increased the rate of dissolution by over six times, and a similar effect was observed with amitriptyline (3 X 10(-3)M), diphenhydramine (3 X 10(-3)M), dicyclomine (3 X 10(-3)M) and propantheline (3 X 10(-3)M). These drugs are as effective as benzalkonium chloride at these concentrations. Amitriptyline, propantheline, dicyclomine and diphenhydramine also increased cholesterol dissolution rates into ox bile. If these drugs are excreted into human bile in sufficient quantities and in an active form they may be able to enhance the speed of cholesterol gallstone dissolution therapy.

Animals↗

PubMed1983

In vitro and in vivo antibacterial activity of AT-2266.

AT-2266 [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carbo xylic acid] showed a broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms, including Pseudomonas aeruginosa. The in vitro antibacterial activity of AT-2266 was in general comparable to that of norfloxacin, but much higher than that of pipemidic or nalidixic acid. The 90% minimal inhibitory concentrations (MIC90s) of AT-2266 for P. aeruginosa resistant to gentamicin (MIC range, 25 to greater than 200 microgram/ml) and Enterobacteriaceae resistant to nalidixic acid (25 to greater than 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The to nalidixic acid (25 to 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The MICs of AT-2266 were only slightly affected by the addition of horse serum or sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was bactericidal at concentrations near its MIC value. The 50% effective doses of AT-2266 after oral administration against systemic infections in mice were about 1/2 those of norfloxacin, about 1/10 those of pipemidic acid, and between 1/20 and 1/40 those of nalidixic acid.

Animals↗

PubMed1981

Effects of pH shifts, bile salts, and glucose on sporulation of Clostridium perfringens NCTC 8798.

The sporulation of Clostridium perfringens NCTC 8798 was studied after exposing vegetative cells to: pH values of 1.5 to 8.0 in fluid thioglycolate broth (for 2h) and then transferring them to Duncan-Strong (DS) sporulation medium; sodium cholate or sodium deoxycholate (0.3 to 6.5 mM) in DS medium; or Rhia-Solberg medium with 0.4% (wt/wt) starch, glucose, or both added at 0 to 55 mM. At pH 1.5, no culturable heat-resistant spores were formed. For cells exposed to pH 3.0, 4.0, 5.0, or 6.0, increases in heat-resistant spores were not seen until after a lag of 12 to 13 h, whereas the lag was only 2 to 3 h for cells exposed to pH 7.0 or 8.0. Maximal spore crops were produced after only 6 to 8 h for cells exposed to pH 7 or 8, but 16 to 18 h was required for production of maximal spore crops by cells exposed to the lower-pH media. The addition of sodium cholate (3.5 to 6.5 mM) to DS medium only slightly reduced the culturable heat-resistant spore count from 1.9 X 10(7) to 3 X 10(6)/ml. The addition of 1.8 mM or more sodium deoxycholate reduced the culturable heat-resistant spore count to less than 10/ ml. When either starch or glucose alone was added to Rhia-Solberg medium there was no production of culturable heat-resistant spores, but a combination of 0.4% (wt/wt) starch and 4.4 mM glucose yielded 6 X 10(5) spores/ml. The spore production remained at this level for glucose concentrations of 6 to 22 mM, but then declined to about 3 X 10(3) spores per ml at higher concentrations.

Cholic Acids↗

PubMed1984

Effect of restricted aeration on catabolism of cholic acid by two Pseudomonas species.

Examination of some previously isolated bile acid-utilizing Pseudomonas strains showed that Pseudomonas sp. ATCC 31752, together with other fluorescent strains, can be assigned to Pseudomonas putida biotype B, whereas Pseudomonas sp. ATCC 31753, like most other nonfluorescent strains, is an unrecognized phenotype. A study was made of the growth of these two species at 25 degrees C and pH 7.0 in a fermentor with 2.5 g of sodium cholate liter-1 as sole carbon source, and the catabolism of the cholate and its products was followed by high-pressure liquid chromatographic and thin-layer chromatographic examination. At aeration rates of either 150 or 5 ml min-1 liter-1, growth of each species followed the same catabolic pathway. 7 alpha, 12 beta-Dihydroxy-1,4-androstadiene-3,17-dione was the major catabolite formed, with 0.3 g liter-1 being the maximum concentration that accumulated at the higher aeration rate, whereas 1.4 g liter-1 accumulated at the lower aeration rate, irrespective of the species used. The latter yield is sufficiently high to be of potential commercial value if such a catabolite were found to be economically useful for steroid drug manufacture. It is postulated that the rate-limiting step in cholic acid catabolism by these species at the lower aeration rate is 9 alpha-hydroxylation, a step requiring molecular oxygen, hence, the marked effect of oxygen limitation on catabolite accumulation. Another consequence of oxygen limitation is the production of a red pigment in the culture medium, which, however, does not affect catabolite recovery.

Aerobiosis↗

PubMed1975

Multiple forms of 7-alpha-hydroxysteroid dehydrogenase in selected strains of Bacteroides fragilis.

Multiple forms of 7-alpha-hydroxysteroid dehydrogenase were detected in six of nine strains of Bacteroides fragilis. The enzymes differed with respect to pyridine nucleotide specificity, thermal stability, divalent metal cation requirement, and elution profilies from Sephadex G-200 columns. The nicotinamide adenine dinucleotide phosphate (NADP)-dependent enzyme required divalent metal cations, preferentially Mn-2+ (Km, 57 muM), for maximum catalytic activity. The NADP-dependent enzyme was labile at 65 C for 10 min, whereas the nicotinamide adenine dinucleotide (NAD)-dependent enzyme was stable at 65 C for 10 min. The specific activity of both the NAD- and NADP-dependent enzymes in crude extracts increased markedly (15- and 7.5-fold, respectively) during the transition from exponential- to stationary-phase growth in glucose medium containing 0.5 mM sodium cholate. The time course of apparent enzyme induction correlated temporally with the transformation of the 7-alpha-hydroxy group of cholate in the culture supernatant fluid. Both NAD- and NADP-dependent 7-alpha-hydroxysteroid dehydrogenase activities were found to be widely, but not universally, distributed in different strains and subspecies of B. fragilis. No NAD- or NADP-dependent 7-alpha-hydroxysteroid dehydrogenase activity could be detected in B. fragilis subsp. vulgatus Virginia Polytechnic Institute (VPI) no. 4245, subsp. thetaiotaomicron VPI 0061-1, or subsp. distasonis VPI 4243.

Bacteroides↗

PubMed1992

Identification of a cocaine esterase in a strain of Pseudomonas maltophilia.

A strain of Pseudomonas maltophilia (termed MB11L) which was capable of using cocaine as its sole carbon and energy source was isolated by selective enrichment. An inducible esterase catalyzing the hydrolysis of cocaine to ecgonine methyl ester and benzoic acid was identified and purified 22-fold. In the presence of the solubilizing agent cholate, cocaine esterase had a native Mr of 110,000 and was shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to be a monomer. In the absence of cholate, cocaine esterase had a native Mr of 410,000 and probably existed as a tetramer. The pH optimum of the enzyme was 8.0, and the Km values for cocaine, ethyl benzoate, and ethyl 2-hydroxybenzoate were 0.36, 1.89, and 1.75 mM, respectively. Inhibition studies indicated that the enzyme was a serine esterase, possibly possessing a cation-binding site similar to those of mammalian acetylcholinesterase and the atropine esterase of Pseudomonas putida PMBL-1. The cocaine esterase of P. maltophilia MB11L showed no activity with atropine, despite the structural similarity of cocaine and atropine.

Benzoates↗

PubMed1965

EFFECT OF HIGH FAT DIETS ON INTESTINAL MICROFLORA AND SERUM CHOLESTEROL IN RATS.

Graber, C. D. (Baylor University College of Medicine, Houston, Tex.), R. M. O'Neal, and E. R. Rabin. Effect of high fat diets on intestinal microflora and serum cholesterol in rats. J. Bacteriol. 89:47-51. 1965.-Differential bacterial counts of feces and total plasma cholesterol determinations were performed on 60 Wistar rats fed several high lipid diets for a period of approximately 6 months. Fecal flora remained relatively stable irrespective of diet, but cholesterol levels rose in animals fed butter and sodium cholate. The six most commonly cultured organisms in all diets were enterococci, Proteus, lactobacilli, Escherichia coli, Staphylococcus aureus, and other micrococci. No enteric pathogens which did not ferment lactose or fermented it slowly were grown. Fungi and yeasts were rare. Aerobes generally outnumbered anaerobes in proportions which were sometimes as high as 300:1. Clostridium perfringens isolations were consistently high in animals given the butter diets, particularly when sodium cholate was added. Evidence is reviewed which indicates that this organism may play a role in bile salt and cholesterol metabolism. This experiment would seem to demonstrate that differences in plasma-cholesterol levels among the various dietary groups of rats were the result of dietary factors rather than alteration in intestinal flora.

Animals↗

PubMed1982

Immunological detection of the Kanagawa phenomenon of vibrio parahaemolyticus on modified selective media.

Selective media for Vibrio parahaemolyticus, BTB-Teepol agar and modified arabinose-ammonium sulfate-cholate agar, were modified for use in immunological detection of the thermostable direct hemolysin produced by this organism. The modified BTB-Teepol agar and modified arabinose-ammonium sulfate-cholate agar were both found to be useful for the modified Elek test and immunohalo test with antiserum (or immunoglobulin G) against the thermostable direct hemolysin. With these modified media it is possible to isolate V. parahaemolyticus and identify the Kanagawa phenomenon on a single plate and thus save time in obtaining results.

Culture Media↗

PubMed1973

Regulation of bile salt pool size in man.

When the enterohepatic circulation is intact the size of the bile salt pool is largely determined by the frequency of its enterohepatic circulation. This hypothesis, derived from studies of cholate kinetics in coeliac, cholecystectomy, and gall stone patients, represents the simplest interpretation of the data. A corollary is that daily cholate secretion is likely to be normal in these conditions and that therefore the propensity of bile to form cholesterol gall stones is not likely to be directly related to bile salt pool size.

Bile↗

PubMed1980

Bile salt transport in the Dubin-Johnson syndrome.

Serum bile salt measurements and intravenous clearance of glycocholate were performed in a woman with Dubin-Johnson syndrome. Fasting conjugated cholate concentration was raised and prolonged intravenous clearance of sodium glycocholate revealed a secondary rise in conjugated cholate concentration after two hours. The intravenous clearance of bromsulphthalein also showed a secondary rise. These findings support the proposal that Dubin-Johnson syndrome is not homogeneous and that in some patients a abnormality of bile salt clearance coexists with an abnormality of bilirubin nd bromsulphthalein clearance.

Aged↗

PubMed1979

Radioimmunoassay of primary bile salts in serum.

Rapid, sensitive radioimmunoassays have been developed for the conjugated primary bile salts, cholate and chenodeoxycholate, using immunogens prepared by the mixed anhydride procedure. Antibodies produced showed equal specificity for glycine and taurine conjugates. Cross-reactivities were comparable with those from other published radioimmunoassays. The assays were routinely performed on unextracted sera and the concentrations correlated well with concentrations determined by gas-liquid chromatography. Accuracy, determined by the addition of bile salt to charcoal-extracted serum, and percision, determined by replicate analysis of a normal sample, were both less than +/- 10%. These figures are comparable with those obtained by both gas-liquid chromatography and other radioimmunoassays for bile salts. Normal sera were found to contain 0.49-1.32 mumol/l of cholate and 0.55-2.02 mumol/l of chenodeoxycholate. Serum concentrations in patients with liver disease were higher than this normal range. Three patients with mild liver distrubance were found to have one bile salt in the upper limit of normal, but in each case the other primary bile salt was outwith the normal range.

Adult↗

PubMed1990

Cholesterol absorption by the gall bladder.

Model and real biles were used to investigate factors influencing cholesterol and dextran (70,000 molecular weight) absorption by the gall bladder. Cholesterol absorption was proportional to cholesterol concentration when real bile was used, but model biles showed maximal absorption at cholesterol saturation. Reduction of temperature reduced cholesterol absorption and serosal secretion, but had little effect on dextran absorption. This indicates differences in uptake where cholesterol undergoes passive diffusion but dextran is taken up by fluid-phase endocytosis. Model bile prepared with a single bile salt showed lowest cholesterol uptake from cholate bile, but there was no difference in serosal secretion. Dextran uptake was also lowest from cholate bile, although serosal secretion was highest. These results show that an increase in the biliary content of dihydroxy bile salts increases gall bladder permeability to both hydrophobic and hydrophilic molecules and may lead to the accumulation of lipids in the mucosa, as seen in cholesterolosis.

Absorption↗

PubMed1990

Alterations of bile acid and bumetanide uptake during culturing of rat hepatocytes.

Uptake by the multispecific bile acid transport system of [3H]taurocholate, [14C]cholate, and [3H]-bumetanide into primary cultures of rat hepatocytes was compared with their uptake into freshly isolated rat hepatocytes. The uptake maximum velocity (Vmax) of all compounds declined in primary culture, whereas the Michaelis constant (Km) values remained stable. Loss of uptake was not due to the reduction of driving forces as evaluated from the level of ATP and the activity of Na(+)-K(+)-ATPase. No alpha-fetoprotein was detectable in culture supernatants. Neither growth factors (glycylhistidyl-lysine, epidermal growth factor), peroxisome and cell proliferators (nafenopin, dimethyl sulfoxide), nor bile acids prevented the loss of transport in hepatocyte culture. However, addition of dibutyryl adenosine 3'5'-cyclic monophosphate protracted the transport activity significantly. When cultured rat hepatocytes with reduced transport were detached by trypsin, cells rounded up and showed the same uptake capacity for bumetanide, cholate, and taurocholate as seen in freshly isolated hepatocytes. "Cryptic" transport activity in the lower basolateral membrane facing the support was found using an incubation chamber for cultured hepatocytes, which allowed us to distinguish simultaneously between uptake via the upper and lower basolateral membrane of the cultured cells.

Adenosine Triphosphate↗

PubMed2005

Bile acid signaling through FXR induces intracellular adhesion molecule-1 expression in mouse liver and human hepatocytes.

Previous studies have demonstrated a dramatic induction of inflammatory gene expression in livers from mice fed a high-fat, high-cholesterol diet containing cholate after 3-5 wk. To determine the contribution of cholate in mediating these inductions, C57BL/6 mice were fed a chow diet supplemented with increasing concentrations of cholic acid (CA) for 5 days. A dose-dependent induction in the hepatic levels of TNF-alpha, VCAM-1, ICAM-1, and SAA-2 mRNA were observed. As positive controls, a dose-dependent repression of cholesterol 7alpha-hydroxylase and a dose-dependent induction of small heterodimer partner (SHP) expression were also observed, suggesting that farnesoid X receptor (FXR) was activated. In addition, ICAM-1 and SHP mRNA levels were also induced in primary human hepatocytes when treated with chenodeoxycholic acid or GW4064, a FXR-selective agonist. The involvement of FXR in CA-induced inflammatory gene expression was further investigated in the human hepatic cell line HepG2. Both ICAM-1 and SHP expression were induced in a dose- and time-dependent manner by treatment with the FXR-selective agonist GW4064. Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA. Finally, the activity of FXR was mapped to a retinoic acid response element (RARE) site containing an imbedded farnesoid X response element (FXRE) on the human ICAM-1 promoter and FXR and retinoid X receptor were demonstrated to bind to this site. Finally, FXR-mediated activation of ICAM-1 could be further enhanced by TNF-alpha cotreatment in hepatocytes, suggesting a potential cooperation between cytokine and bile acid-signaling pathways during hepatic inflammatory events.

Animals↗

PubMed2006

Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep.

Na(+)-taurocholate-cotransporting peptide (NTCP)/SLC10A1 and bile salt export pump (BSEP)/ABCB11 synergistically play an important role in the transport of bile salts by the hepatocyte. In this study, we transfected human NTCP and BSEP or rat Ntcp and Bsep into LLC-PK1 cells, a cell line devoid of bile salts transporters. Transport by these cells was characterized with a focus on substrate specificity between rats and humans. The basal to apical flux of taurocholate across NTCP- and BSEP-expressing LLC-PK1 monolayers was 10 times higher than that in the opposite direction, whereas the flux across the monolayer of control and NTCP or BSEP single-expressing cells did not show any vectorial transport. The basal to apical flux of taurocholate was saturated with a K(m) value of 20 microM. Vectorial transcellular transport was also observed for cholate, chenodeoxycholate, ursodeoxycholate, their taurine and glycine conjugates, and taurodeoxycholate and glycodeoxycholate, whereas no transport of lithocholate was detected. To evaluate the respective functions of NTCP and BSEP and to compare them with those of rat Ntcp and Bsep, we calculated the clearance by each transporter in this system. A good correlation in the clearance of the examined bile salts (cholate, chenodeoxycholate, ursodeoxycholate, and their taurine or glycine conjugates) was observed between transport by human and that of rat transporters in terms of their rank order: for NTCP, taurine conjugates > glycine conjugates > unconjugated bile salts, and for BSEP, unconjugated bile salts and glycine conjugates > taurine conjugates. In conclusion, the substrate specificity of human and rat NTCP and BSEP appear to be very similar at least for monovalent bile salts under physiological conditions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1980

Fetal bile salt metabolism: placental transfer of taurocholate in sheep.

Bidirectional placental transfer of taurocholate was studied in conscious, pregnant sheep near term. In studies of maternal-to-fetal transfer sodium, [14C]cholate was injected intravenously daily into the mother to label the endogenous cholate pool. Ninety-five percent of the radiolabel was present in the maternal pool as [14C]taurocholate. No radiolabel was detected in the fetal bile over 6-9 days, indicating minimal placental transfer of taurocholate to the fetus. In contrast, mean fetal-to-maternal transfer of taurocholate, studied over 3-4 days, was 2.6 mumol/24 h, representing approximately 2%/day of the fetal taurocholate pool. We conclude that in the sheep placental transfer from the mother, at term, contributes little if any taurocholate to the fetal pool. However, the placenta may be an important excretory organ for fetal bile salts, thus playing a key role in fetal steriol homeostasis.

Animals↗

PubMed1987

Identification of a single sinusoidal bile salt uptake system in skate liver.

To identify the sinusoidal bile acid uptake system(s) of skate liver, photoaffinity labeling and kinetic transport studies were performed in isolated plasma membranes as well as intact hepatocytes. In both preparations photoaffinity labeling with the photolabile bile salt derivative (7,7-azo-3 alpha, 12 alpha-dihydroxy-5 beta-[3 beta-3H]cholan-24-oyl)-2-aminoethanesulfonate revealed the presence of a predominant bile salt binding polypeptide with an apparent molecular weight of 54,000. The labeling of this polypeptide was inhibited by taurocholate and cholate in a concentration-dependent manner and was virtually abolished by 1 mM of the anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Kinetic studies of hepatic uptake with taurocholate, cholate, and the photoreactive bile salt derivative indicated the involvement of a single transport system, and all three substrates mutually competed with the uptake of each other. Finally, irreversible inhibition of the bile salt uptake system by photoaffinity labeling of hepatocytes with high concentrations (250 microM) of photolabile derivative reduced the Vmax but not the Km of taurocholate uptake. These findings strongly indicate that a single polypeptide with an apparent molecular weight of 54,000 is involved in sinusoidal bile salt uptake into skate hepatocytes. These findings contrast with similar studies in rat liver that implicate both a 54,000- and 48,000-K polypeptide in bile salt uptake and are consistent with a single Na+-independent transport mechanism for hepatic bile salt uptake in this primitive vertebrate.

Affinity Labels↗