Cholesterol solubilization by oxo derivatives of selected bile acids and their membranotoxicity

2010 ◽  
Vol 75 (8) ◽  
pp. 767-784 ◽  
Author(s):  
Mihalj Poša ◽  
Zita Farkaš
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Critical Micellar Concentration ◽  
Group I ◽  
Cholesterol Solubilization ◽  
The Common ◽  
Osmotic Resistance Of Erythrocytes ◽  
Derivatives Of ◽  
Solubilizing Capacity ◽  
Steroid Skeleton

This study is concerned with the effect of the structure of bile acids on the solubilization of cholesterol (cholesterol solubilizing capacity (CChm) and the equilibrium micellary solubilization of cholesterol (xChm)). It was found that the replacement of the hydroxy group in the bile acid molecule with an oxo group results in a decrease of the solubilization power of cholesterol. The examined bile acids form two linear groups at the plane of critical micellar concentration (CMC) and solubilization power of cholesterol (CChm or xChm). The group I is formed by bile acids with lower CMCs and higher cholesterol solubilites (deoxycholic (1), chenodeoxycholic (2), hyodeoxycholic (3), cholic (8), 12-oxolithocholic (4), and 7-oxolithocholic (5) acids). On the other hand, the group II is formed by bile acids with higher CMCs and lower cholesterol solubilites (7-oxodeoxycholic (9), 12-oxochenodeoxycholic (10), 12α-hydroxy-3,7-dioxocholanic (11), 7,12-dioxolithocholic (12), 3,7-dioxocholanic (6), and 3,12-dioxocholanic (7) acids). The common conformational characteristics of the bile acid molecules was determined (orientation of OH or oxo grups considered to the mean plane of the steroid skeleton). They form joint groups in the plane of CMC – (CChm or xChm), and the linear function (CChm or xChm) = f(CMC). The osmotic resistance of erythrocytes determines the membranotoxicity of bile acids. 12-Oxolithocholic acid represents the best compromise with regard to the solubilization of cholesterol and membranotoxicity.

Bile acid structure and bile formation: a comparison of hydroxy and keto bile acids

1980 ◽  
Vol 238 (1) ◽  
pp. G10-G17 ◽  
Author(s):  
R. B. Sewell ◽  
N. E. Hoffman ◽  
R. A. Smallwood ◽  
S. Cockbain
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Critical Micellar Concentration ◽  
Bile Formation ◽  
Phospholipid Ratio ◽  
Alpha 7 ◽  
Water Secretion ◽  
Cholesterol Secretion ◽  
Solubilizing Capacity

The effect of four bile acids, taurocholic (TC), taurochenodeoxycholic (TCDC), tauro-3 alpha,7 alpha-dihydroxy-12-keto-5 beta-cholanoic (T12K), and cholic (C), on bile lipid and water secretion was studied in the bile fistula cat over a 20-fold range of bile acid secretion rates. The critical micellar concentration (CMC) and lecithin-solubilizing capacity of TC, TCDC, and T12K were measured in vitro. T12K and C produced a greater choleresis than TC or TCDC; phospholipid secretion was strikingly reduced with T12K; and cholesterol secretion strikingly increased with TCDC, with a high cholesterol-phospholipid ratio. The estimated CMCs of TC, TCDC, and T12K were 3.3, 0.7, and 6.2 mM respectively; the relative lecithin-solubilizing capacities were 4.4:2.6:1. We conclude that the micellar characteristics of the bile acids studied do not explain the differences in water and lipid secretion observed, and that effects within the hepatocyte may be equally important.

Differing effects of norcholate and cholate on bile flow and biliary lipid secretion in the rat

1984 ◽  
Vol 246 (1) ◽  
pp. G67-G71
Author(s):  
E. R. O'Maille ◽  
S. V. Kozmary ◽  
A. F. Hofmann ◽  
D. Gurantz
Keyword(s):  
Bile Acid ◽  
Acid Secretion ◽  
Bile Acids ◽  
Bile Flow ◽  
Critical Micellar Concentration ◽  
Biliary Lipid ◽  
Lipid Secretion ◽  
Unit Increase ◽  
Cholesterol Secretion ◽  
Bile Acid Secretion

The effects of norcholate (a C23 bile acid that differs from cholate in having a side chain containing four rather than five carbon atoms) on bile flow and biliary lipid secretion were compared with those of cholate, using the anesthetized rat with a bile fistula. Norcholate and cholate were infused intravenously over the range of 0.6-6.0 mumol X min-1 X kg-1. Both bile acids were quantitatively secreted into bile; norcholate was secreted predominantly in unconjugated form in contrast to cholate, which was secreted predominantly as its taurine or glycine conjugates. The increase in bile flow per unit increase in bile acid secretion induced by norcholate infusion [17 +/- 3.2 (SD) microliters/mumol, n = 8] was much greater than that induced by cholate infusion (8.6 +/- 0.9 microliters/mumol, n = 9) (P less than 0.001). Both bile acids induced phospholipid and cholesterol secretion. For an increase in bile acid secretion (above control values) of 1 mumol X min-1 X kg-1, the increases in phospholipid secretion [0.052 +/- 0.024 (SD) mumol X min-1 X kg-1, n = 9] and cholesterol secretion (0.0071 +/- 0.0033 mumol X min-1 X kg-1, n = 9) induced by norcholate infusion were much less than those induced by cholate infusion (0.197 +/- 0.05 mumol X min-1 X kg-1, n = 9, and 0.024 +/- 0.011 mumol X min-1 X kg-1, n = 9, respectively; P less than 0.001 for both phospholipid and cholesterol). The strikingly different effects of norcholate on bile flow and biliary lipid secretion were attributed mainly to its possessing a considerably higher critical micellar concentration than cholate.

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)

Influence of side-chain charge on hepatic transport of bile acids and bile acid analogues

1985 ◽  
Vol 249 (4) ◽  
pp. G479-G488 ◽  
Author(s):  
M. S. Anwer ◽  
E. R. O'Maille ◽  
A. F. Hofmann ◽  
R. A. DiPietro ◽  
E. Michelotti
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Liver Cell ◽  
Hepatic Uptake ◽  
Biliary Secretion ◽  
Side Chain ◽  
Bile Fistula ◽  
Bile Acid Derivatives ◽  
Derivatives Of ◽  
Secretion Rates

The importance of side-chain charge on hepatic uptake and biliary secretion of bile acids and analogues was studied using the isolated, perfused rat liver and the anesthetized rat with a bile fistula. Derivatives of cholic acid with negative, neutral, zwitterionic, or positive charges on the side chain were synthesized and studied. Hepatic uptake by the isolated perfused liver, determined by measuring the rate of disappearance of a single 20-mumol bolus added to the perfusate, was strongly influenced by side-chain charge. A fully positively charged bile acid derivative (cholylcholamine) and two fully zwitterionic bile acid derivatives (CHAPS and cholyllysine) showed no appreciable uptake (less than 1% of the uptake rate of cholyltaurine). Bile acid derivatives existing mostly in cationic form (cholylamine) at pH 7.4, in neutral form (cholylglycylhistamine), or in divalent anion form (cholylaspartate and cholylcysteate) had an uptake rate that was greater but only 7-19% that of cholyltaurine. Side-chain charge also appeared to influence the rate of secretion into bile. Bile acids existing in mono- or dianionic form were well secreted (greater than 95% of dose in 2 h) into the bile, but all other derivatives had much lower secretion rates (less than 20% of dose in 2 h). When the biliary secretion of each bile acid derivative was expressed in relation to the amount that had entered the liver, relative secretion rates (presumably from liver cell) into bile decreased in the following order: cholyltaurine greater than cholylaspartate and cholylcysteate greater than CHAPS greater than cholyllysine greater than cholylglycylhistamine approximately equal to cholylamine. In bile fistula rats, cholylaspartate was quantitatively secreted into bile when infused at rates below its secretory maximum, whereas only very low biliary secretion rates of CHAPS were observed even during relatively high infusion rates; cholylamine was cholestatic. The above data show that, although uncharged and anionic derivatives of cholic acid may be taken up by the liver at a moderate rate, only anionic derivatives (both monovalent and divalent) are well secreted from within the liver cell into bile. A single negative charge on the side chain appears to be required for optimal transport of a bile acid from sinusoidal blood to bile.

What is meant by the term "bile acid"?

1983 ◽  
Vol 244 (2) ◽  
pp. G107-G110
Author(s):  
L. Roger ◽  
J. St Pyrek ◽  
J. M. Little ◽  
E. W. Adcock
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Group ◽  
Side Chain ◽  
Diverse Group ◽  
Carboxylic Acid Group ◽  
Naturally Occurring ◽  
Intensive Investigation ◽  
Definition Of ◽  
Derivatives Of

The bile acids are a set of acidic steroids. Many conventional bile acids share a common derivation and have functional characteristics in common. Exceptions exist, however, to virtually all of the rules that can be applied to a definition of bile acids. The term is thus best applied to those steroids with a side chain at C-17, which contains a carboxylic acid group, and to acidic derivatives of such compounds. Naturally occurring bile acids are a more numerous and diverse group than has been generally recognized. The site of origin, synthetic pathways, metabolism, and bioactivity of recently recognized unconventional bile acids are under intensive investigation.

Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione

2006 ◽  
Vol 290 (4) ◽  
pp. G640-G649 ◽  
Author(s):  
Maria Rius ◽  
Johanna Hummel-Eisenbeiss ◽  
Alan F. Hofmann ◽  
Dietrich Keppler
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Reduced Glutathione ◽  
Membrane Vesicles ◽  
Multidrug Resistance Protein ◽  
Bile Salt Export Pump ◽  
Physiological Conditions ◽  
Resistance Protein ◽  
The Common ◽  
Inside Out

The multidrug resistance protein ABCC4 (MRP4), a member of the ATP-binding cassette superfamily, mediates ATP-dependent unidirectional efflux of organic anions out of cells. Previous studies showed that human ABCC4 is localized to the sinusoidal membrane of hepatocytes and mediates, among other substrates, the cotransport of reduced glutathione (GSH) with bile acids. In the present study, using inside-out membrane vesicles, we demonstrated that human ABCC4 in the presence of physiological concentrations of GSH has a high affinity for the taurine and glycine conjugates of the common natural bile acids as well as the unconjugated bile acid cholate. Chenodeoxycholyltaurine and chenodeoxycholylglycine were the GSH cosubstrates with the highest affinities for ABCC4, with Km values of 3.6 and 5.9 μM, respectively. Ursodeoxycholyltaurine and ursodeoxycholylglycine were cotransported together with GSH by ABCC4 with Km values of 7.8 and 12.5 μM, respectively, but no transport of ursodeoxycholate and deoxycholate was observed. The simultaneous transport of labeled GSH and cholyltaurine or cholylglycine was demonstrated in double-labeled cotransport experiments with a bile acid-to-GSH ratio of ∼1:22. Km values of the bile acids for ABCC4 were in a range similar to those reported for the canalicular bile salt export pump ABCB11. Under physiological conditions, the sinusoidal ABCC4 may compete with canalicular ABCB11 for bile acids and thereby play a key role in determining the hepatocyte concentration of bile acids. In cholestatic conditions, ABCC4 may become a key pathway for efflux of bile acids from hepatocytes into blood.

scholarly journals Bile acids as constituents for dental composites: in vitro cytotoxicity of (meth)acrylate and other ester derivatives of bile acids

2007 ◽  
Vol 4 (17) ◽  
pp. 1145-1150 ◽  
Author(s):  
Marc A Gauthier ◽  
Pierre Simard ◽  
Zhao Zhang ◽  
X.X Zhu
Keyword(s):  
Bile Acids ◽  
Entire Range ◽  
Degradation Products ◽  
Dental Materials ◽  
In Vitro Cytotoxicity ◽  
Dental Composites ◽  
3T3 Fibroblasts ◽  
The Common ◽  
Derivatives Of

Methacrylic derivatives of bile acids have been synthesized for use as monomers in dental composites. Polymeric dental materials are known to leach cytotoxic unreacted monomers and degradation products. In this study, the in vitro cytotoxicity of bile acids and their derivatives towards 3T3 fibroblasts has been evaluated by colorimetric MTT assay and compared with that of the common dental monomers BisGMA, UDMA and TEGDMA. In general, the bile acids and their derivatives induced mitochondrial dysfunction at similar or higher concentrations than the commercial dental monomers. Certain monomers did not influence MTT response over their entire range of solubility.

Pharmacological effects of secondary bile acid microparticles in diabetic murine model

2020 ◽  
Vol 16 ◽  
Author(s):  
Armin Mooranian ◽  
Nassim Zamani ◽  
Bozica Kovacevic ◽  
Corina Mihaela Ionescu ◽  
Giuseppe Luna ◽  
...  
Keyword(s):  
Bile Acid ◽  
Blood Glucose ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Diabetes Treatment ◽  
Secondary Bile Acid ◽  
Glucose Levels ◽  
Anti Inflammatory ◽  
Antidiabetic Effects

Aim: Examine bile acids effects in Type 2 diabetes. Background: In recent studies, the bile acid ursodeoxycholic acid (UDCA) has shown potent anti-inflammatory effects in obese patients while in type 2 diabetics (T2D) levels of the pro-inflammatory bile acid lithocholic acid were increased, and levels of the anti-inflammatory bile acid chenodeoxycholic acid were decreased, in plasma. Objective: Hence, this study aimed to examine applications of novel UDCA nanoparticles in diabetes. Methods: Diabetic balb/c adult mice were divided into three equal groups and gavaged daily with either empty microcapsules, free UDCA, or microencapsulated UDCA over two weeks. Their blood, tissues, urine, and faeces were collected for blood glucose, inflammation, and bile acid analyses. UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Results: UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Conclusion: Bile acids modulated the bile profile without affecting blood glucose levels.

scholarly journals Manipulating the Microbiome: An Alternative Treatment for Bile Acid Diarrhoea

2021 ◽  
Vol 12 (2) ◽  
pp. 335-353
Author(s):  
Evette B. M. Hillman ◽  
Sjoerd Rijpkema ◽  
Danielle Carson ◽  
Ramesh P. Arasaradnam ◽  
Elizabeth M. H. Wellington ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Gastrointestinal Disease ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Metabolism ◽  
The United Kingdom ◽  
The 1960S ◽  
Irritable Bowel ◽  
The Uk

Bile acid diarrhoea (BAD) is a widespread gastrointestinal disease that is often misdiagnosed as irritable bowel syndrome and is estimated to affect 1% of the United Kingdom (UK) population alone. BAD is associated with excessive bile acid synthesis secondary to a gastrointestinal or idiopathic disorder (also known as primary BAD). Current licensed treatment in the UK has undesirable effects and has been the same since BAD was first discovered in the 1960s. Bacteria are essential in transforming primary bile acids into secondary bile acids. The profile of an individual’s bile acid pool is central in bile acid homeostasis as bile acids regulate their own synthesis. Therefore, microbiome dysbiosis incurred through changes in diet, stress levels and the introduction of antibiotics may contribute to or be the cause of primary BAD. This literature review focuses on primary BAD, providing an overview of bile acid metabolism, the role of the human gut microbiome in BAD and the potential options for therapeutic intervention in primary BAD through manipulation of the microbiome.

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