Preparation of the 3-monosulphates of cholic acid, chenodeoxycholic acid and deoxycholic acid.
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ABSTRACT:
SUBMITTER: Haslewood ES
PROVIDER: S-EPMC1172846 | biostudies-other | 1976 May
REPOSITORIES: biostudies-other
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Project description:Bile acids are powerful detergents that emulsify and solubilize lipids, vitamins, cholesterol and other molecules in the biliary tract and intestines. It has long been known that bile acids form soluble mixed micelles with lipids. However, the detailed thermodynamic and structural properties of these micelles are not fully understood. This study sheds light on this issue based on results from multiple molecular dynamics simulations of cholic acid (CA) and dodecylphosphocholine (DPC) mixed micelles. We found that CA molecules form aggregates of up to 12 monomers with a mean size of 5-6. In agreement with several previous simulations and earlier predictions, the overall shape of these CA clusters is oblate disk-like such that the methyl groups point toward the core of the aggregate and the hydroxyl groups point away from it. The self-aggregation behavior of the CA clusters in the DPC-CA mixture is similar to the pure CA. Furthermore, the sizes and aggregation numbers of the DPC-CA mixed micelles are linearly dependent on CA molarity. In agreement with the radial shell model of Nichols and Ozarowski [Nichols, J. W.; Ozarowski, J. Biochemistry 1990, 29, 4600], our results demonstrate that CA molecules form a wedge between the DPC molecules with their hydroxyl and carboxyl groups facing the aqueous phase while their methyl groups are buried in and face the hydrocarbon core of the DPC micelle. The DPC-CA micelles simulated here tend to be spherical to prolate in shape, with the deviation from spherical geometry significantly increasing with increasing CA:DPC ratio.
| S-EPMC2924285 | biostudies-literature
Project description:In the title inclusion compound, 2C(24)H(40)O(5)·C(8)H(6)N(2), the unit cell contains two mol-ecules of cholic acid (3?,7?,12?-trihydr-oxy-5?-cholan-24-oic acid) and one mol-ecule of quinoxaline which implies disorder of the quinoxaline in the space group P2(1). The amphiphilic mol-ecules of cholic acid assemble, in an anti-parallel arrangement, via O-H?O hydrogen bonds, into typical corrugated host bilayers which are lipophilic on the outside and lipophobic on the inside. The host framework belongs to the so called ?-trans subtype. The quinoxaline mol-ecules are accommodated in lipophilic channels formed between neighboring bilayers with only van der Waals inter-actions between host and guest. There is a crystallographic twofold screw axis directed along an empty channel in the host framework; however, neighboring guests in any one channel are related by a unit-cell translation along the b axis. Thus, the overall structure is a 1:1 superposition of two such channels related by the crystallographic twofold screw axis.
| S-EPMC2961426 | biostudies-literature
Project description:IntroductionZellweger spectrum disorders (ZSDs) are characterized by a failure in peroxisome formation, caused by autosomal recessive mutations in different PEX genes. At least some of the progressive and irreversible clinical abnormalities in patients with a ZSD, particularly liver dysfunction, are likely caused by the accumulation of toxic bile acid intermediates. We investigated whether cholic acid supplementation can suppress bile acid synthesis, reduce accumulation of toxic bile acid intermediates and improve liver function in these patients.MethodsAn open label, pretest-posttest design study was conducted including 19 patients with a ZSD. Participants were followed longitudinally during a period of 2.5 years prior to the start of the intervention. Subsequently, all patients received oral cholic acid and were followed during 9 months of treatment. Bile acids, peroxisomal metabolites, liver function and liver stiffness were measured at baseline and 4, 12 and 36 weeks after start of cholic acid treatment.ResultsDuring cholic acid treatment, bile acid synthesis decreased in the majority of patients. Reduced levels of bile acid intermediates were found in plasma and excretion of bile acid intermediates in urine was diminished. In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates.ConclusionsOral cholic acid therapy can be used in the majority of patients with a ZSD, leading to at least partial suppression of bile acid synthesis. However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects.
| S-EPMC5065608 | biostudies-literature
Project description:In this study, we assessed the potential use of the 1β-hydroxy-deoxycholic acid (1β-OH-DCA) to deoxycholic acid (DCA) urinary metabolic ratio (UMR) as a CYP3A metric in ten male healthy volunteers. Midazolam (MDZ) 1 mg was administered orally at three sessions: alone (control session), after pre-treatment with fluvoxamine 50 mg (12 h and 2 h prior to MDZ administration), and voriconazole 400 mg (2 h before MDZ administration) (inhibition session), and after a 7-day pre-treatment with the inducer rifampicin 600 mg (induction session). The 1β-OH-DCA/DCA UMR was measured at each session, and correlations with MDZ metrics were established. At baseline, the 1β-OH-DCA/DCA UMR correlated significantly with oral MDZ clearance (r = 0.652, p = 0.041) and Cmax (r = -0.652, p = 0.041). In addition, the modulation of CYP3A was reflected in the 1β-OH-DCA/DCA UMR after the intake of rifampicin (induction ratio = 11.4, p < 0.01). During the inhibition session, a non-significant 22% decrease in 1β-OH-DCA/DCA was observed (p = 0.275). This result could be explained by the short duration of CYP3A inhibitors intake fixed in our clinical trial. Additional studies, particularly involving CYP3A inhibition for a longer period and larger sample sizes, are needed to confirm the 1β-OH-DCA/DCA metric as a suitable CYP3A biomarker.
| S-EPMC7923269 | biostudies-literature
Project description:Bile acids are critical contributors to the regulation of whole body glucose homeostasis; however, the mechanisms remain incompletely defined. While the hydrophilic bile acid subtype, ursodeoxycholic acid, has been shown to attenuate hepatic endoplasmic reticulum (ER) stress and thereby improve glucose regulation in mice, the effect of hydrophobic bile acid subtypes on ER stress and glucose regulation in vivo is unknown. Therefore, we investigated the effect of the hydrophobic bile acid subtype, deoxycholic acid (DCA), on ER stress and glucose regulation. Eight week old C57BL/6J mice were fed a high fat diet supplemented with or without DCA. Glucose regulation was assessed by oral glucose tolerance and insulin tolerance testing. In addition, circulating bile acid profile and hepatic insulin and ER stress signaling were measured. DCA supplementation did not alter body weight or food intake, but did impair glucose regulation. Consistent with the impairment in glucose regulation, DCA increased the hydrophobicity of the circulating bile acid profile, decreased hepatic insulin signaling and increased hepatic ER stress signaling. Together, these data suggest that dietary supplementation of DCA impairs whole body glucose regulation by disrupting hepatic ER homeostasis in mice.
| S-EPMC6066200 | biostudies-literature
Project description:Two cultures, one grown on cholic acid and the other on pyruvate.
2011-03-29 | GSE28048 | GEO
Project description:Zellweger spectrum disorders (ZSDs), a subgroup of peroxisomal biogenesis disorders, have a generalized defect in peroxisome function. Liver disease in ZSDs has been linked to accumulation of C27-bile acid intermediates due to the lack of peroxisomal ?-oxidation of these intermediates to form primary C24-bile acids. Oral treatment with primary bile acid, cholic acid (CA), inhibits formation of hepatotoxic C27-bile acids by restoring normal physiologic feedback inhibition on bile acid synthesis. We present the long-term CA treatment and liver-related outcomes for 3 pediatric patients with ZSDs who have received CA treatment for ?15 years. Ongoing CA treatment was associated with stabilized liver function, as shown by serum biochemistries and liver histopathology, and no treatment-related adverse effects were observed. All 3 patients have attended regular school with classroom accommodations and attained a good quality of life. Our patient outcomes suggest that early and ongoing CA therapy may sustain liver function in patients with ZSDs.
| S-EPMC6062720 | biostudies-literature
Project description:The emergence of multidrug-resistant microbes is a significant health concern posing a constant need for new antimicrobials. Membrane-targeting antibiotics are promising candidates with reduced ability of microbes to develop resistance. In the present investigation, the principal reason behind choosing cholic acid as the crucial scaffold lies in the fact that it has a facially amphiphilic nature, which provides ample opportunity to refine the amphiphilicity by linking the amino acid lysine. A total of 16 novel amphipathic cholic acid derivatives were synthesized by sequentially linking lysine to C3-β-amino cholic acid methyl ester to maintain the hydrophobic/hydrophilic balance, which could be the essential requirement for the antimicrobial activity. Among the synthesized conjugates, a series with fluorenyl-9-methoxycarbonyl moiety attached to cholic acid via lysine linker showed promising antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans. A pronounced effect of increase in lysine residues was noted on the observed activity. The lead compounds were found to be active against drug-resistant bacterial and fungal clinical isolates and also improved the efficacy of antifungal agents amphotericin B and voriconazole. Membrane-permeability studies demonstrated the ability of these compounds to induce membrane damage in the tested microbes. The active conjugates did not show any hemolytic activity and were also found to be nontoxic to the normal cells as well as the examined cancer cell lines. The observed antimicrobial activity was attributed to the facial amphiphilic conformations, hydrophobic/hydrophilic balance, and the overall charge on the molecules.
| S-EPMC7057326 | biostudies-literature
Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat chronic pain and inflammation. However, prolonged use of NSAIDs has been known to result in Gastrointestinal (GI) ulceration/bleeding, with a bile-mediated mechanism underlying their toxicity to the lower gut. Bile acids (BAs) and phosphatidylcholines (PCs), the major components of bile, form mixed micelles to reduce the membrane disruptive actions of monomeric BAs and simple BA micelles. NSAIDs are suspected to alter the BA/PC balance in the bile, but the molecular interactions of NSAID-BA or NSAID-BA-PC remain undetermined. In this work, we used a series of all-atom molecular dynamics simulations of cholic acid (CA), ibuprofen (IBU) and dodecylphosphocholine (DPC) mixtures to study the spontaneous aggregation of CA and IBU as well as their adsorption on a DPC micelle. We found that the size of CA-IBU mixed micelles varies with their molar ratio in a non-linear manner, and that micelles of different sizes adopt similar shapes but differ in composition and internal interactions. These observations are supported by NMR chemical shift changes, NMR ROESY crosspeaks between IBU and CA, and dynamic light scattering experiments. Smaller CA-IBU aggregates were formed in the presence of a DPC micelle due to the segregation of CA and IBU away from each other by the DPC micelle. While the larger CA-IBU aggregates arising from higher IBU concentrations might be responsible for NSAID-induced intestinal toxicity, the absence of larger CA-IBU aggregates in the presence of DPC micelles may explain the observed attenuation of NSAID toxicity by PCs.
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Project description:There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure-activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.
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