Role of amidation in bile acid effect on DNA synthesis by regenerating mouse liver

1995 ◽  
Vol 268 (6) ◽  
pp. G1051-G1059
Author(s):  
E. R. Barbero ◽  
M. C. Herrera ◽  
M. J. Monte ◽  
M. A. Serrano ◽  
J. J. Marin
Keyword(s):  
Bile Acid ◽  
Dna Synthesis ◽  
Bile Acids ◽  
High Performance ◽  
Cell Injury ◽  
Intraperitoneal Administration ◽  
Inhibitory Effect ◽  
Toxicity Tests ◽  
Maximal Effect

Effect of bile acids on DNA synthesis by the regenerating liver was investigated in mice in vivo after partial hepatectomy (PH). Radioactivity incorporation into DNA after [14C]thymidine intraperitoneal administration peaked at 48 h after PH. At this time a significant taurocholate-induced dose-dependent reduction in DNA synthesis without changes in total liver radioactivity content was found (half-maximal effect at approximately 0.1 mumol/g body wt). Effect of taurocholate (0.5 mumol/g body wt) was mimicked by chocolate, ursodeoxycholate, deoxycholate, dehydrocholate, tauroursodeoxycholate, taurochenodeoxycholate, and taurodeoxycholate. In contrast, chenodeoxycholate, glycocholate, glycochenodeoxycholate, glycoursodeoxycholate, glycodeoxycholate, 5 beta-cholestane, bromosulfophthalein, and free taurine lacked this effect. No relationship between hydrophobic-hydrophilic balance and inhibitory effect was observed. Analysis by high-performance liquid chromatography indicated that inhibition of thymidine incorporation into DNA was not accompanied by an accumulation of phosphorylated DNA precursors in the liver but rather by a parallel increase in nucleotide catabolism. Bile acid-induced modifications in DNA synthesis were observed in vivo even in the absence of changes in toxicity tests, which suggests that the inhibitory effect shared by most unconjugated and tauroconjugated bile acids but not by glycoconjugated bile acids should be accounted for by mechanisms other than nonselective liver cell injury.

FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade

2005 ◽  
Vol 288 (1) ◽  
pp. G60-G66 ◽  
Author(s):  
Hai Li ◽  
Frank Chen ◽  
Quan Shang ◽  
Luxing Pan ◽  
Benjamin L. Shneider ◽  
...  
Keyword(s):  
Bile Acid ◽  
Binding Site ◽  
Bile Acids ◽  
Promoter Activity ◽  
Deoxycholic Acid ◽  
Inhibitory Effect ◽  
Cis Acting ◽  
Regulatory Cascade

The regulation of the rabbit apical sodium-dependent bile acid transporter (ASBT) was studied both in vivo and in vitro. New Zealand White rabbits were fed 0.5% deoxycholic acid (DCA) or SC-435, a competitive ASBT inhibitor, for 1 wk. In DCA-fed rabbits, ASBT expression was repressed, associated with activated FXR, and evidenced by increased ileal short heterodimer partner (SHP) mRNA. Feeding SC-435 to the rabbits blocked bile acid absorption, decreased SHP mRNA, and increased ASBT expression. A 1.9-kb rabbit ASBT 5′-flanking region (promoter) was cloned, and a cis-acting element for α-fetoprotein transcription factor (FTF) was identified (−1166/ −1158). The effects of transcriptional factors and different bile acids on the rabbit ASBT promoter were studied in Caco-2 cells. FTF stimulated the rabbit ASBT promoter activity fourfold but not after the FTF binding site was deleted from the promoter. Increasing the SHP protein notably inhibited FTF-dependent trans-activation of rabbit ASBT. Adding hydrophobic bile acids deoxycholic acid, chenodeoxycholic acid, and cholic acid, activating ligands for FXR, inhibited rabbit ASBT promoter activity in Caco-2 cells, but this inhibitory effect was abolished after the FTF binding site was deleted. Ursodeoxycholic acid and ursocholic acid, nonactivating ligands for FXR, did not repress ASBT promoter activity. Thus the rabbit ASBT promoter is negative-feedback regulated by bile acids via a functional FTF binding site. Only FXR-activating ligands can downregulate rabbit ASBT expression through the regulatory cascade FXR-SHP-FTF.

Effects of Bile Salt Deconjugation by Probiotic Strains on the Survival of Antibiotic-Resistant Foodborne Pathogens under Simulated Gastric Conditions

2012 ◽  
Vol 75 (6) ◽  
pp. 1090-1098 ◽  
Author(s):  
XINLONG HE ◽  
YUNYUN ZOU ◽  
YOUNGJAE CHO ◽  
JUHEE AHN
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Foodborne Pathogens ◽  
Antibiotic Susceptibility ◽  
High Performance ◽  
Bifidobacterium Longum ◽  
Lactobacillus Rhamnosus ◽  
Antibiotic Resistant ◽  
Study Results ◽  
Probiotic Strains

This study was designed to evaluate the effects of bile acid deconjugation by probiotic strains on the antibiotic susceptibility of antibiotic-sensitive and multiple antibiotic–resistant Salmonella Typhimurium and Staphylococcus aureus. Eight probiotic strains, Bifidobacterium longum B6, Lactobacillus acidophilus ADH, Lactobacillus brevis KACC 10553, Lactobacillus casei KACC 12413, Lactobacillus paracasei ATCC 25598, Lactobacillus rhamnosus GG, Leuconostoc mesenteroides KACC 12312, and Pediococcus acidilactici KACC 12307, were used to examine bile acid tolerance. The ability to deconjugate bile acids was evaluated using both thin-layer chromatography and high-performance liquid chromatography. The antibiotic susceptibility testing was carried out to determine the synergistic inhibitory activity of deconjugated bile acids. L. acidophilus, L. brevis, and P. acidilactici showed the most tolerance to the conjugated bile acids. P. acidilactici deconjugated glycocholic acid and glycodeoxycholate from 3.18 and 3.09 mM to the detection limits, respectively. The antibiotic susceptibility of selected foodborne pathogens was increased by increasing the concentration of deconjugated bile acids. The study results are useful for understanding the relationship between bile acid deconjugation by probiotic strains and antibiotic susceptibility in the presence of deconjugated bile acids, and they may be useful for designing new probiotic-antibiotic combination therapy based on bile acid deconjugation.

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.

In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6

2021 ◽  
Vol 36 (4) ◽  
pp. 259-270
Author(s):  
Boon Hooi Tan ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Iekhsan Othman ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Performance ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Time Curve ◽  
Clinical Drugs ◽  
Inhibition Potencies ◽  
P450 2D6

Abstract Objectives Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. Methods CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. Results The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. Conclusions Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

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 Taurolithocholate-induced Ca2+ release is inhibited by phorbol esters in isolated hepatocytes

1992 ◽  
Vol 287 (3) ◽  
pp. 891-896 ◽  
Author(s):  
L Combettes ◽  
B Berthon ◽  
M Claret
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Phorbol Ester ◽  
Phorbol Esters ◽  
Rat Hepatocytes ◽  
Isolated Hepatocytes ◽  
Inhibitory Effect ◽  
Cell Uptake ◽  
Intracellular Binding ◽  
Pkc Activation

The monohydroxy bile acid taurolithocholate (TLC) causes a rapid and transient increase in free cytosolic Ca2+ concentration ([Ca2+]i) in suspensions of rat hepatocytes similar to that elicited by the InsP3-dependent hormone vasopressin. The effect of the bile acid is due to a mobilization of Ca2+, independent of InsP3, from the endoplasmic reticulum (ER). Short-term preincubation of cells with the phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), which activates protein kinase C (PKC), blocked the increase in [Ca2+]i induced by TLC, but did not alter that mediated by vasopressin. We obtained the following results, indicating that the effect of PMA is mediated by the activation of PKC. (1) Phorbol esters were effective over a concentration range where they activate PKC (IC50 = 0.5 nM); (2) phorbol esters that do not activate PKC did not inhibit the effects of TLC; (3) the permeant analogue oleoylacetylglycerol mimicked the inhibitory effect of PMA; (4) lastly, the inhibition of the TLC-induced Ca2+ mobilization by phorbol esters was partially prevented by preincubating the cells with the PKC inhibitors H7 and AMG-C16. Preincubating hepatocytes with PMA had no effect on the cell uptake of labelled TLC, indicating that the phorbol ester does not interfere with the transport system responsible for the accumulation of bile acids. In saponin-treated liver cells, PMA added before or after permeabilization failed to abolish TLC-induced Ca2+ release from the ER. The possibility is discussed that PMA, via PKC activation, may alter the intracellular binding or the transfer of bile acids in the liver.

scholarly journals Biogeography of microbial bile acid transformations along the murine gut

2020 ◽  
Vol 61 (11) ◽  
pp. 1450-1463 ◽  
Author(s):  
Solenne Marion ◽  
Lyne Desharnais ◽  
Nicolas Studer ◽  
Yuan Dong ◽  
Matheus D. Notter ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Pool Size ◽  
Host Signaling ◽  
Gut Microorganisms ◽  
Gut Microbial Community

Bile acids, which are synthesized from cholesterol by the liver, are chemically transformed along the intestinal tract by the gut microbiota, and the products of these transformations signal through host receptors, affecting overall host health. These transformations include bile acid deconjugation, oxidation, and 7α-dehydroxylation. An understanding of the biogeography of bile acid transformations in the gut is critical because deconjugation is a prerequisite for 7α-dehydroxylation and because most gut microorganisms harbor bile acid transformation capacity. Here, we used a coupled metabolomic and metaproteomic approach to probe in vivo activity of the gut microbial community in a gnotobiotic mouse model. Results revealed the involvement of Clostridium scindens in 7α-dehydroxylation, of the genera Muribaculum and Bacteroides in deconjugation, and of six additional organisms in oxidation (the genera Clostridium, Muribaculum, Bacteroides, Bifidobacterium, Acutalibacter, and Akkermansia). Furthermore, the bile acid profile in mice with a more complex microbiota, a dysbiosed microbiota, or no microbiota was considered. For instance, conventional mice harbor a large diversity of bile acids, but treatment with an antibiotic such as clindamycin results in the complete inhibition of 7α-dehydroxylation, underscoring the strong inhibition of organisms that are capable of carrying out this process by this compound. Finally, a comparison of the hepatic bile acid pool size as a function of microbiota revealed that a reduced microbiota affects host signaling but not necessarily bile acid synthesis. In this study, bile acid transformations were mapped to the associated active microorganisms, offering a systematic characterization of the relationship between microbiota and bile acid composition.

Bile duct cells: a novel in vitro model for the study of lipid metabolism and bile acid production

1999 ◽  
Vol 276 (2) ◽  
pp. G407-G414 ◽  
Author(s):  
Monika Zoltowska ◽  
Edgard E. Delvin ◽  
Khazal Paradis ◽  
Ernest Seidman ◽  
Emile Levy
Keyword(s):  
Bile Acid ◽  
Bile Duct ◽  
Bile Acids ◽  
Cytokeratin 19 ◽  
Sterol Metabolism ◽  
Hmg Coa Reductase ◽  
Biliary Epithelium ◽  
Duct Cells ◽  
Coa Reductase

Immortalized bile duct cells (BDC), derived from transgenic mice harboring the SV40 thermosensitive immortalizing mutant gene ts458, were utilized to investigate the role of the biliary epithelium in lipid and sterol metabolism. This cell model closely resembles the in vivo situation because it expresses the specific phenotypic marker cytokeratin 19 (CK-19), exhibits the formation of bile duct-like structures, and displays well-formed microvilli projected from the apical side to central lumen. The BDC were found to incorporate [14C]oleic acid (in nmol/mg protein) into triglycerides (121 ± 6), phospholipids (PL; 59 ± 3), and cholesteryl ester (16 ± 1). The medium lipid content represented 5.90 ± 0.16% ( P < 0.005) of the total intracellular production, indicating a limited lipid export capacity. Analysis of PL composition demonstrated the synthesis of all classes of polar lipids, with phosphatidylcholine and phosphatidylethanolamine accounting for 60 ± 1 and 24 ± 1%, respectively, of the total. Differences in PL distribution were apparent between cells and media. Substantial cholesterol synthesis was observed in BDC, as determined by the incorporation of [14C]acetate suggesting the presence of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. With the use of [14C]acetate and [14C]cholesterol as precursors, both tauro- and glycoconjugates of bile acids were synthesized, indicating the presence of cholesterol 7α- and 26R-hydroxylases, the key enzymes involved in bile acid formation. The transport of bile acids was not limited, as shown by their marked accumulation in the medium (>6-fold of cell content). HMG-CoA reductase (53.0 ± 6.7), cholesterol 7α-hydroxylase (15.5 ± 0.5), and acyl-CoA:cholesterol acyltransferase (ACAT; 201.7 ± 10.2) activities (in pmol ⋅ min−1 ⋅ mg protein−1) were present in the microsomal fractions. Our data show that biliary epithelial cells actively synthesize lipids and may directly contribute bile acids to the biliary fluid in vivo. This BDC line thus represents an efficient experimental tool to evaluate biliary epithelium sterol metabolism and to study biliary physiology.

Sodium cromoglycate: evidence of tachykinin antagonist activity in the human skin

1993 ◽  
Vol 75 (1) ◽  
pp. 167-172 ◽  
Author(s):  
D. C. Crossman ◽  
M. R. Dashwood ◽  
G. W. Taylor ◽  
R. Wellings ◽  
R. W. Fuller
Keyword(s):  
Sodium Cromoglycate ◽  
Human Skin ◽  
High Performance ◽  
Gel Filtration ◽  
Inhibitory Effect ◽  
Intradermal Injection ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

The mechanism of action of the antiasthmatic drug sodium cromoglycate (SCG) is unclear. One possibility is that SCG antagonizes the effects of the tachykinin substance P (SP), an agent known to cause airway edema. However, when SP is inhaled by humans, it has no demonstrable effect on airway function; therefore, the possibility that SCG prevents SP-induced changes in microvascular permeability was examined in human skin in vivo where potent edema-producing effects are seen. SCG (5–500 nmol) caused significant (P < 0.05) dose-dependent inhibition of SP-induced edema (wheal) formation when coadministered by intradermal injection. There was no effect on the nonreceptor-mediated flare response. SCG also significantly (P < 0.05) inhibited the wheal response to the related tachykinin neurokinin B but had no inhibitory effect on the cutaneous responses to histamine and prostaglandin E2. In addition, SCG (0.1–10 mM) caused dose-dependent inhibition of binding of SP labeled with 125I-labeled Bolton-Hunter to a number of tissues known to contain SP binding sites, as assessed by autoradiography. These concentrations were equivalent to the final concentrations of SCG found to inhibit the wheal response in the skin. The possibility that SCG interacted with SP was investigated both by gel filtration and high-performance liquid chromatography. No strong interaction was demonstrated with an 8,000 M excess of SCG under both hydrophobic and hydrophilic conditions. These results raise the possibility that SCG may have tachykinin antagonist properties.

scholarly journals α-Glucosidase Inhibitory, Anti-Oxidant, and Anti-Hyperglycemic Effects of Euphorbia nivulia–Ham. in STZ-Induced Diabetic Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582093942
Author(s):  
Muhammad Younus ◽  
Muhammad Mohtasheem ul Hasan ◽  
Khalil Ahmad ◽  
Ali Sharif ◽  
Hafiz Muhammad Asif ◽  
...  
Keyword(s):  
High Performance ◽  
Wistar Rat ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Control Group ◽  
Control Drug ◽  
Antidiabetic Effects

In this study, we aimed to investigate the antidiabetic effects of Euphorbia nivulia (En), native to Cholistan Desert area of Bahawalpur, Pakistan. First, we performed high-performance liquid chromatography analysis and found that this plant contains ferulic acid, gallic acid, quercetin, benzoic acid, polyphenols, and flavonoids. Then, we performed in vitro and in vivo studies to assess its effects on diabetic Wistar rat model. The experiments were performed and compared with control drug glibenclamide. The 70% hydroalcoholic extract of En exhibited 97.8% in vitro α-glucosidase inhibitory effect at a dose of 1.0 mg/mL. We orally administered the extract of En and control drug to the streptozotocin (STZ)-induced diabetic rats and analyzed its antidiabetic effects. We found that the extract of En with a dose of 500 mg/kg/body weight exhibited significant effect to reduce blood glucose in STZ-induced rats as compared with the control group ( P < .001). Our histological data also showed that the extract significantly improved the histopathology of pancreas. Collectively, both in vitro and in vivo studies revealed that En possesses α-glucosidase inhibitory, antioxidant, and anti-hyperglycemic effect in STZ-induced diabetic rats.

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