Deoxycholic Acid Conjugates Are Muscarinic Cholinergic Receptor Antagonists
Abstract
In the course of examining the actions of major human bile acids on cholinergic receptors, we discovered that conjugates of lithocholic acid are partial muscarinic agonists. In the present communication, we report that conjugates of deoxycholic acid (DC) act as cholinergic muscarinic receptor antagonists. Chinese hamster ovary (CHO) cells expressing rat M3-muscarinic receptors were used to test bile acids for inhibition of radioligand [N- 3 H-methylscopolamine (3 H-NMS)] binding; alteration of inositol phosphate (IP) formation; mitogen-activated protein (MAP) kinase phosphorylation and cell toxicity. We observed approximately 18.8, 30.3 and 37.1% inhibition of 3 H-NMS binding with DC and its glycine (DCG) and taurine (DCT) conjugates, respectively (all 100 µmol/l, p < 0.01). DCT and DCG inhibited acetylcholine-induced increases in IP formation and MAP kinase phosphorylation (p44 and p42 ERK). DCG and DCT did not alter trypan blue exclusion or lactate dehydrogenase release from CHO-M3 cells. We observed the following rank order of potency (IC 50 µmol/l) for inhibition of 3 H-NMS by muscarinic antagonists and bile acids: NMS (0.0004) > 4-DAMP (0.009) > atropine (0.012) > DCT (170) > DCG (250). None of the bile acids tested were hydrolyzed by recombinant cholinesterase. At concentrations achieved in human bile, DC derivatives are natural muscarinic antagonists.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Secondary bile acids can also exert similar negative chronotropic effects, though at lower concentrations relative to primary bile acids even in cholestatic states.
“Though at lower concentrations relative to primary bile acids even in cholestatic states, secondary bile acids can also exert similar effects.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [133]
Primary bile acids exert direct negative myocardial chronotropic effects in a dose-dependent fashion.
“Early studies of primary bile acids have been shown to exert direct negative myocardial chronotropic effects in a dose-dependent fashion132,133.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [133]
Cites
LIGAND: A versatile computerized approach for characterization of ligand-binding systems
Munson, P. J., & Rodbard, D. (1980) · Analytical Biochemistry · doi:10.1016/0003-2697(80)90515-1 · Cited by 8,494 · see citing works
Identification of a nuclear receptor for bile acids
Makishima, M., Okamoto, A. Y., Repa, J. J., Tu, H., Learned, R. M., Luk, A., Hull, M. V., Lustig, K. D., Mangelsdorf, D. J., & Shan, B. (1999) · Science · doi:10.1126/science.284.5418.1362 · Cited by 2,714 · see citing works
Bile Acids: Natural Ligands for an Orphan Nuclear Receptor
Parks, D. J., Blanchard, S. G., Bledsoe, R. K., Chandra, G., Consler, T. G., Kliewer, S. A., Stimmel, J. B., Willson, T. M., Zavacki, A. M., Moore, D. D., et al. (1999) · Science · doi:10.1126/science.284.5418.1365 · Cited by 2,274 · see citing works
Identification of a Family of Muscarinic Acetylcholine Receptor Genes
Bonner, T. I., Buckley, N. J., Young, A. C., & Brann, M. R. (1987) · Science · doi:10.1126/science.3037705 · Cited by 1,427 · see citing works
Alpini, G. D., Lenzi, R., Sárközi, L., & Tavoloni, N. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113355 · Cited by 333 · see citing works
Alpini, G. D., Glaser, S. S., Ueno, Y., Rodgers, R., Phinizy, J. L., Francis, H., Baiocchi, L., Holcomb, L. A., Caligiuri, A., & LeSage, G. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70242-8 · Cited by 185 · see citing works
Chapter 12: Muscarinic acetylcholine receptor subtypes: localization and structure/function
Brann, M. R., Ellis, J., Jørgensen, H. B., Hill‐Eubanks, D. C., & Jones, S. V. P. (1993) · Progress in brain research · doi:10.1016/s0079-6123(08)62388-2 · Cited by 100 · see citing works
Mechanisms of phospholipase D stimulation by m3 muscarinic acetylcholine receptors
Schmidt, M., HÜWe, S. M., Fasselt, B., et al. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.00667.x · Cited by 95 · see citing works
The muscarinic receptor gene expressed in rabbit parietal cells is the m3 subtype
Kajimura, M., Reuben, M. A., & Sachs, G. M. (1992) · Gastroenterology · doi:10.1016/0016-5085(92)90019-u · Cited by 82 · see citing works
Ryan, R. R., Weber, H. C., Hou, W., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13613 · Cited by 78 · see citing works
Raufman, J., Zimniak, P., & Bartoszko‐Malik, A. (1998) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1998.274.6.g997 · Cited by 39 · see citing works
Self-citationCharacterization of cholinergic receptors mediating pepsinogen secretion from chief cells
Sutliff, V. E., Rattan, S. C., Gardner, J. D., et al. (1989) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1989.257.2.g226 · Cited by 27 · see citing works
Hepatic extraction of bile salts in conscious dogs.
Pries, J. M., Sherman, C. A., Williams, G. C., et al. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.236.2.e191 · Cited by 25 · see citing works
Cation-anion gap and choleretic properties of rat bile.
Klos, C., Paumgartner, G., & Reichen, J. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.236.4.e434 · Cited by 24 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dietary metabolism, the gut microbiome, and heart failure
Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
Bile Acid-Activated Receptors, Intestinal Microbiota, and the Treatment of Metabolic Disorders
Fiorucci, S., & Distrutti, E. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2015.09.001 · Cited by 539 · see citing works
The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation
Pols, T. W. H., Noriega, L. G., Nomura, M., Auwerx, J., & Schoonjans, K. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2010.12.004 · Cited by 454 · see citing works
The bile acid membrane receptor TGR5: a valuable metabolic target
Pols, T. W. H., Noriega, L. G., Nomura, M., Auwerx, J., & Schoonjans, K. (2011) · Digestive Diseases · doi:10.1159/000324126 · Cited by 185 · see citing works
Baars, A., Oosting, A., Knol, J., Garssen, J., & Van Bergenhenegouwen, J. (2015) · Microorganisms · doi:10.3390/microorganisms3040641 · Cited by 135 · see citing works
Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors
Keitel, V., Stindt, J., & Häussinger, D. (2019) · Handbook of Experimental Pharmacology · doi:10.1007/164_2019_230 · Cited by 98 · see citing works
- Authors
- Raufman, J.-P., Chen, Y., Zimniak, P., & Cheng, K.
- Affiliations
- Central Arkansas Veterans Healthcare System (US)
- Venue
- Pharmacology
- Publisher
- S. Karger AG
- Published
- 2002
- Volume
- 65
- Issue
- 4
- Pages
- 215-221
- ISSN
- 0031-7012 (ISSN-L)
- 1423-0313
- OpenAlex
- W2026123068
- Cited by
- 47
- References
- 14
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- deoxycholic acid, bile acids, antimuscarinic agents, M3 muscarinic receptor, cholinergic receptors, inositol phosphate formation, bile acid conjugates
- MeSH terms
- Animals, Bile Acids and Salts, Cell Membrane, Cholinesterases, Deoxycholic Acid, Dose-Response Relationship, Drug, Female, Glycine, Cricetinae, Humans, Inositol Phosphates, Phosphorylation, Radioligand Assay, Receptors, Muscarinic, Taurine, CHO Cells, Cholinergic Agonists, Muscarinic Antagonists, Mitogen-Activated Protein Kinases, Receptor, Muscarinic M3, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
