SK&F 97426-A: A Novel Bile Acid Sequestrant with Higher Affinities and Slower Dissociation Rates for Bile Acids in vitro Than Cholestyramine

1997 ◽  
Vol 86 (1) ◽  
pp. 76-81 ◽  
Author(s):  
G. Martin Benson ◽  
David R. Alston ◽  
Deirdre M.B. Hickey ◽  
Albert A. Jaxa-Chamiec ◽  
Caroline M. Whittaker ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Bile Acid Sequestrant

scholarly journals Evaluating Hepatobiliary Transport with 18F-Labeled Bile Acids: The Effect of Radiolabel Position and Bile Acid Structure on Radiosynthesis and In Vitro and In Vivo Performance

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stef De Lombaerde ◽  
Ken Kersemans ◽  
Sara Neyt ◽  
Jeroen Verhoeven ◽  
Christian Vanhove ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Membrane Vesicles ◽  
Hepatic Uptake ◽  
Hepatobiliary Transport ◽  
Bile Acid Transporters ◽  
Significant Difference ◽  
The Impact

Introduction. An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n=3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c.) and high radiochemical purity (>99%); 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.

scholarly journals Downregulation of CTRP-3 by Weight Loss In Vivo and by Bile Acids and Incretins in Adipocytes In Vitro

2020 ◽  
Vol 21 (21) ◽  
pp. 8168
Author(s):  
Andreas Schmid ◽  
Jonas Gehl ◽  
Miriam Thomalla ◽  
Alexandra Hochberg ◽  
Anja Kreiß ◽  
...  
Keyword(s):  
Weight Loss ◽  
Bile Acid ◽  
Bile Acids ◽  
Serum Levels ◽  
Receptor Expression ◽  
Low Calorie Diet ◽  
Calorie Diet ◽  
Bile Acid Receptor

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system.

scholarly journals Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

2019 ◽  
Author(s):  
Pavan Bhargava ◽  
Leah Mische ◽  
Matthew D. Smith ◽  
Emily Harrington ◽  
Kathryn C Fitzgerald ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
White Matter Lesions ◽  
The Body ◽  
Bile Acid Metabolism ◽  
Dependent Manner ◽  
Microglial Polarization

AbstractMultiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

scholarly journals Retention of Primary Bile Acids by Lupin Cell Wall Polysaccharides Under In Vitro Digestion Conditions

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2117 ◽  
Author(s):  
Naumann ◽  
Schweiggert-Weisz ◽  
Haller ◽  
Eisner
Keyword(s):  
Cell Wall ◽  
Bile Acid ◽  
Bile Acids ◽  
Molecular Interactions ◽  
Enterohepatic Circulation ◽  
In Vitro Digestion ◽  
Adsorptive Capacity ◽  
Cell Wall Polysaccharides ◽  
Dietary Fibres

Interference of dietary fibres with the enterohepatic circulation of bile acids is proposed as a mechanism for lowering cholesterol. We investigated how lupin hull and cotyledon dietary fibres interact with primary bile acids using an in vitro model under simulated upper gastrointestinal conditions. Cell wall polysaccharides were isolated and extracted to separate pectin-like, hemicellulosic, and lignocellulosic structures. Lupin hull consisted mainly of structural components rich in cellulose. The viscosity of the in vitro digesta of lupin hull was low, showing predominantly liquid-like viscoelastic properties. On the other hand, lupin cotyledon fibre retarded bile acid release due to increased viscosity of the in vitro digesta, which was linked with high contents of pectic polymers forming an entangled network. Molecular interactions with bile acids were not measured for the hull but for the cotyledon, as follows: A total of 1.29 µmol/100 mg DM of chenodesoxycholic acids were adsorbed. Molecular interactions of cholic and chenodesoxycholic acids were evident for lignin reference material but did not account for the adsorption of the lupin cotyledon. Furthermore, none of the isolated and fractionated cell wall materials showed a significant adsorptive capacity, thus disproving a major role of lupin cell wall polysaccharides in bile acid adsorption.

scholarly journals In Vitro Interactions of Dietary Fibre Enriched Food Ingredients with Primary and Secondary Bile Acids

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1424 ◽  
Author(s):  
Susanne Naumann ◽  
Ute Schweiggert-Weisz ◽  
Julia Eglmeier ◽  
Dirk Haller ◽  
Peter Eisner
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Dietary Fibre ◽  
In Vitro Digestion ◽  
Food Ingredients ◽  
Bile Acid Pool Size ◽  
As Adsorption ◽  
Secondary Bile Acids ◽  
In Vitro Interactions

Dietary fibres are reported to interact with bile acids, preventing their reabsorption and promoting their excretion into the colon. We used a method based on in vitro digestion, dialysis, and kinetic analysis to investigate how dietary fibre enriched food ingredients affect the release of primary and secondary bile acids as related to viscosity and adsorption. As the main bile acids abundant in humans interactions with glyco- and tauroconjugated cholic acid, chenodesoxycholic acid and desoxycholic acid were analysed. Viscous interactions were detected for apple, barley, citrus, lupin, pea, and potato derived ingredients, which slowed the bile acid release rate by up to 80%. Adsorptive interactions of up to 4.7 μmol/100 mg DM were significant in barley, oat, lupin, and maize preparations. As adsorption directly correlated to the hydrophobicity of the bile acids the hypothesis of a hydrophobic linkage between bile acids and dietary fibre is supported. Delayed diffusion in viscous fibre matrices was further associated with the micellar properties of the bile acids. As our results indicate changes in the bile acid pool size and composition due to interactions with dietary fibre rich ingredients, the presented method and results could add to recent fields of bile acid research.

scholarly journals In vitro evidence that phosphatidylcholine protects against indomethacin/bile acid-induced injury to cells

2015 ◽  
Vol 308 (3) ◽  
pp. G217-G222 ◽  
Author(s):  
Elizabeth J. Dial ◽  
Paul A. Dawson ◽  
Lenard M. Lichtenberger
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cell Injury ◽  
Cell Damage ◽  
Protective Mechanism ◽  
Acid Uptake ◽  
Intestinal Epithelial ◽  
Acute Cytotoxicity ◽  
Serious Injury

Indomethacin is a powerful analgesic nonsteroidal anti-inflammatory drug (NSAID), but is limited in use by its primary side effect to cause gastrointestinal bleeding and serious injury. One factor important for exacerbating NSAID injury is the presence of bile acids, which may interact with indomethacin to form toxic mixed micelles in the gut. The development of a safer gastrointestinal formulation of indomethacin that is chemically complexed with phosphatidylcholine (PC-indomethacin) may offer an improved therapeutic agent, particularly in the presence of bile acid, but its potential protective mechanism is incompletely understood. Intestinal epithelial cells (IEC-6) were tested for injury with indomethacin (alone and plus various bile acids) compared with PC-indomethacin (alone and plus bile acids). To explore a role for bile acid uptake into cells as a requirement for NSAID injury, studies were performed using Madin-Darby canine kidney cells transfected with the apical sodium-dependent bile acid transporter (ASBT). Indomethacin, but not PC-indomethacin, was directly and dose-dependently injurious to IEC-6 cells. Similarly, the combination of any bile acid plus indomethacin, but not PC-indomethacin, induced cell injury. The expression of ASBT had a modest effect on the acute cytotoxicity of indomethacin in the presence of some conjugated bile acids. Complexing PC with indomethacin protected against the acute intestinal epithelial injury caused by indomethacin regardless of the presence of bile acids. The presence of luminal bile acid, but not its carrier-mediated uptake into the enterocyte, is required for acute indomethacin-induced cell injury. It is likely that initial cell damage induced by indomethacin occurs at or near the cell membrane, an effect exacerbated by bile acids and attenuated by PC.

Differing effects of hydroxy-7-oxotaurine-conjugated bile acids on bile flow and biliary lipid secretion in dogs

1984 ◽  
Vol 246 (2) ◽  
pp. G166-G172
Author(s):  
R. G. Danzinger ◽  
M. Nakagaki ◽  
A. F. Hofmann ◽  
E. B. Ljungwe
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Bile Flow ◽  
Critical Micellar Concentration ◽  
Independent Effect ◽  
Biliary Lipid ◽  
Compound I ◽  
Lipid Secretion ◽  
The Individual

The effects on bile flow and biliary lipid secretion of two taurine-conjugated 7-oxo bile acids, 3 alpha-hydroxy-7-oxocholanoyltaurine (I) and 3 alpha,12 alpha-dihydroxy-7-oxocholanoyltaurine (II), were measured in the unanesthetized, chronic bile fistula dog. Each synthetically prepared compound, or cholyltaurine as control, was infused intravenously at a physiological rate of 1 mumol X kg-1 X min-1 for randomized 90-min periods. Bile samples were collected and analyzed for biliary lipids (bile acids, phospholipid, and cholesterol) and bile acid composition. Both compounds were secreted efficiently in bile, recovery averaging 90%. The trisubstituted compound (II) induced a greater choleresis and less phospholipid and cholesterol secretion than the disubstituted compound (I) or cholyltaurine. Each oxo compound was partially reduced during hepatic passage: about 47% of I (to mostly chenodeoxycholyltaurine) and about 30% of II (to mostly cholyltaurine). The effect of the individual bile acids on biliary lipid secretion was then calculated by assuming that a) the infused bile acid induced biliary lipid secretion after its hepatic biotransformation and b) each bile acid or its biotransformation product exerted an independent effect on biliary lipid secretion (expressed as a linkage coefficient, e.g., phospholipid secretion/bile acid secretion). For phospholipid, the calculated linkage coefficient for I was 0.31; for II, 0.07. For cholesterol, the calculated linkage coefficient for I was 0.014; for II, 0.003. In vitro studies indicated that the critical micellar concentration (CMC) in 0.15 M Na+ was 22 mM for I and 40 mM for II (compared with 6 mM for cholyltaurine.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals The Role of Inflammation in the Mechanisms of Bile Acid-Induced Liver Damage

2017 ◽  
Vol 35 (3) ◽  
pp. 232-234 ◽  
Author(s):  
Shi-Ying Cai ◽  
James L. Boyer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Bile Acids ◽  
Liver Damage ◽  
Inflammatory Cytokine ◽  
Early Time ◽  
Liver Cells ◽  
Wild Type Littermate

Background: The mechanism by which bile acids induce liver injury in cholestasis remains controversial. Although high levels of bile acids are toxic when applied to liver cells, the level of toxic bile acids in the liver of most cholestatic animals and patients is <10 μM, indicating there must be alternative mechanisms. Recent studies suggest that the inflammatory response may play an important role in bile acid-induced liver injury, as pro-inflammatory cytokine expression is stimulated by bile acids in mouse hepatocyte cultures. To elucidate the mechanisms of bile acid-induced liver injury, we assessed signs of liver damage and gene expression in Abcb4-/- mice, a well-known model for cholestasis. Key Messages: Elevated plasma levels of bile acids were detected as early as 10 days after birth and at all later ages in Abcb4-/- mice compared to their wild-type littermate controls. Parallel increases in expression of Tnfα, Ccl2, Cxcl1, and Cxcl2 mRNA occurred at these early time points and throughout 12 weeks in Abcb4-/- livers. Marked hepatic neutrophil infiltration was first detected in 3-week mice, whereas histological evidence of liver injury was not detected until 6-weeks of age. Subsequent in vitro studies demonstrated that normal hepatocytes but not other non-parenchymal liver cells responded to bile acids with inflammatory cytokine induction. Conclusion: Bile acids induce the expression of pro-inflammatory cytokines in hepatocytes in Abcb4-/- mice that initiates an inflammatory response. This inflammatory response plays an important role in the development of cholestatic liver injury in this and other cholestatic conditions. Furthermore, understanding of these inflammatory mechanisms should lead to new therapeutic approaches for cholestatic liver diseases.

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