Transport, metabolism, and effect of chronic feeding of lagodeoxycholic acid

Schmassmann, Adrian; Angellotti, M. A.; Clerici, Carlo; Hofmann, A. F.; Ton‐Nu, Huong‐Thu; Schteingart, Claudio D.; Marcus, Samuel F.; Hagey, Lee R.; Rossi, Steven S.; Aigner, A.

doi:10.1016/0016-5085(90)90630-j

Cited by 19 publications

(4 citation statements)

References 61 publications

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“…Natural occurring BAs, BA derivatives, and steroid hormones were purchased from Sigma-Aldrich or Steraloids (Newport, RI) except the following compounds. Lagodeoxycholic acid (3α,12β-dihydroxy-5β-cholan-24-oic acid, lago-DCA, 8 ), 3-dehydrochenodeoxycholic acid (3-oxo-7α-hydroxy-5β-cholan-24-oic acid, 3-dehydro-CDCA, 20 ), 3-deoxychenodeoxycholic acid (7α-hydroxy-5β-cholan-24-oic acid, 3-deoxy-CDCA, 21 ) were synthesized as described previously. – Nor-BAs, 3α-hydroxy-24-nor-5β-cholan-23-oic acid (nor-LCA, 26 ), 3α,7α-dihydroxy-24-nor-5β-cholan-23-oic acid (nor-CDCA, 28 ), and 3α,7β-dihydroxy-24-nor-5β-cholan-23-oic acid (nor-UDCA, 38 ), and dinor-BAs, 3α,7α-dihydroxy-23,24-dinor-5β-cholan-22-oic acid (dinor-CDCA, 29 ) and 3α,7β-dihydroxy-23,24-dinor-5β-cholan-22-oic acid (dinor-UDCA, 39 ), were synthesized by side chain degradation of their corresponding BAs as described previously. , Bile alcohols, 5β-cholane-3α,7α,24-triol (CDC-OH, 30 ), 5β-cholane-3α,7α,12α,24-tetrol (C-OH, 36 ), and 5β-cholane-3α,7β,24-triol (UDC-OH, 40 ), and bile sulfonates, 3α,7α-dihydroxy-5β-cholane-24-sulfonate (CDC-Sul, 31 ), 3α,7α,12α-trihydroxy-5β-cholane-24-sulfonate (C-Sul, 37 ), and 3α,7β-dihydroxy-5β-cholane-24-sulfonate (UDC-Sul, 41 ), were synthesized from the corresponding BAs as described previously – 7-Fluorinated BA derivatives, 7α-fluoro-LCA (3α-hydroxy-7α-fluoro-5β-cholan-24-oic acid, 7α-F-LCA, 18 ) and 7β-fluoro-LCA (3α-hydroxy-7β-fluoro-5β-cholan-24-oic acid, 7β-F-LCA, 19 ), were synthesized as described previously .…”

Section: Methodsmentioning

confidence: 99%

Novel Potent and Selective Bile Acid Derivatives as TGR5 Agonists: Biological Screening, Structure−Activity Relationships, and Molecular Modeling Studies

et al. 2008

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TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.

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Section: Methodsmentioning

confidence: 99%

Novel Potent and Selective Bile Acid Derivatives as TGR5 Agonists: Biological Screening, Structure−Activity Relationships, and Molecular Modeling Studies

et al. 2008

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“…3␤-Hydroxy epimers of CDCA and DCA were prepared by tosylation followed by a dimethylformamide inversion reaction, as described by Iida and Chang (15). The 12␤-hydroxy epimer of DCA was also a gift of Diamalt; its properties have been reported previously (29). 24-norDCA was prepared from DCA as described (30).…”

Section: Methodsmentioning

confidence: 99%

Bile acid-induced secretion in polarized monolayers of T84 colonic epithelial cells: structure-activity relationships

Keely¹,

Scharl²,

Bertelsen³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile acid epimers and side-chain homologues are present in the human colon. To test whether such bile acids possess secretory activity, cultured T84 colonic epithelial cells were used to quantify the secretory properties of synthetic epimers and homologues of deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). In our study, chloride secretion was measured as changes in short-circuit current (DeltaI(sc), in microA/cm2) with the use of voltage-clamped monolayers of T84 cells mounted in Ussing chambers. Bile acids were added at 0.5 mM, a concentration that did not alter transepithelial resistance. Data were expressed as peak DeltaI(sc) (means +/- SD). When added bilaterally, DCA stimulated a DeltaI(sc) response of 15.7 +/- 12.5 microA/cm2. The 12beta-OH epimer of DCA was less potent (DeltaI(sc) = 8.0 +/- 1.7 microA/cm2), whereas its 3beta-OH epimer had no effect. CDCA stimulated secretion (DeltaI(sc) = 8.2 +/- 5.5 microA/cm2), whereas both its 7beta-OH and 3beta-OH epimers were inactive, as was lithocholic acid. HomoDCA (1 additional side-chain carbon) was active (DeltaI(sc) = 7.8 +/- 4.8 microA/cm2), whereas norDCA (1 fewer carbon) and dinorDCA (2 fewer carbons) were not. Taurine conjugates of DCA and CDCA stimulated secretion (DeltaI(sc) = 12.3 +/- 7.5 and 8.8 +/- 4.8 microA/cm2, respectively) from the basolateral side but not the apical side. Uptake of taurine conjugates from the basolateral but not the apical side was shown by mass spectrometry. These studies indicate marked structural specificity for bile acid-induced chloride secretion and show that modification of bile acid structure by colonic bacteria modulates the secretory properties of these endogenous secretagogues.

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“…The ileal Na + /bile acid transport system has also been explored to enhance intestinal peptide absorption. There are certain structural elements that have been identified to be necessary for molecular recognition of a bile acid by the Na + /bile acid transport system. ,, A series of small, linear model peptides of chain length up to 10 amino acids were covalently coupled to the 3-position of a modified bile acid to give peptide−bile acid conjugates which were found to be significantly less susceptible to hydrolysis in comparison to cephalexin conjugates . Conjugation of peptides with bile acid seemed to prevent the access of conjugates to the brush-border peptidases, thus escaping the usual transport and metabolic pathways for peptides.…”

Section: Carrier-mediated Transportmentioning

confidence: 99%