Cargando…

Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research

Novel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibil...

Descripción completa

Detalles Bibliográficos
Autores principales: Robery, Steven, Mukanowa, Janina, Percie du Sert, Nathalie, Andrews, Paul L. R., Williams, Robin S. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169598/
https://www.ncbi.nlm.nih.gov/pubmed/21931717
http://dx.doi.org/10.1371/journal.pone.0024439
_version_ 1782211515728789504
author Robery, Steven
Mukanowa, Janina
Percie du Sert, Nathalie
Andrews, Paul L. R.
Williams, Robin S. B.
author_facet Robery, Steven
Mukanowa, Janina
Percie du Sert, Nathalie
Andrews, Paul L. R.
Williams, Robin S. B.
author_sort Robery, Steven
collection PubMed
description Novel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibility of using the social amoeba, Dictyostelium discoideum, for research into identifying and understanding emetic liability, and hence reduce adverse animal experimentation in this area. Twenty eight emetic or taste aversive compounds were employed to investigate the acute (10 min) effect of compounds on Dictyostelium cell behaviour (shape, speed and direction of movement) in a shallow chemotaxic gradient (Dunn chamber). Compound concentrations were chosen based on those previously reported to be emetic or aversive in in vivo studies and results were recorded and quantified by automated image analysis. Dictyostelium cell motility was rapidly and strongly inhibited by four structurally distinct tastants (three bitter tasting compounds - denatonium benzoate, quinine hydrochloride, phenylthiourea, and the pungent constituent of chilli peppers - capsaicin). In addition, stomach irritants (copper chloride and copper sulphate), and a phosphodiesterase IV inhibitor also rapidly blocked movement. A concentration-dependant relationship was established for five of these compounds, showing potency of inhibition as capsaicin (IC(50) = 11.9±4.0 µM) > quinine hydrochloride (IC(50) = 44.3±6.8 µM) > denatonium benzoate (IC(50) = 129±4 µM) > phenylthiourea (IC(50) = 366±5 µM) > copper sulphate (IC(50) = 1433±3 µM). In contrast, 21 compounds within the cytotoxic and receptor agonist/antagonist classes did not affect cell behaviour. Further analysis of bitter and pungent compounds showed that the effect on cell behaviour was reversible and not cytotoxic, suggesting an uncharacterised molecular mechanism of action for these compounds. These results therefore demonstrate that Dictyostelium has potential as a non-sentient model in the analysis of the molecular effects of tastants, although it has limited utility in identification of emetic agents in general.
format Online
Article
Text
id pubmed-3169598
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-31695982011-09-19 Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research Robery, Steven Mukanowa, Janina Percie du Sert, Nathalie Andrews, Paul L. R. Williams, Robin S. B. PLoS One Research Article Novel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibility of using the social amoeba, Dictyostelium discoideum, for research into identifying and understanding emetic liability, and hence reduce adverse animal experimentation in this area. Twenty eight emetic or taste aversive compounds were employed to investigate the acute (10 min) effect of compounds on Dictyostelium cell behaviour (shape, speed and direction of movement) in a shallow chemotaxic gradient (Dunn chamber). Compound concentrations were chosen based on those previously reported to be emetic or aversive in in vivo studies and results were recorded and quantified by automated image analysis. Dictyostelium cell motility was rapidly and strongly inhibited by four structurally distinct tastants (three bitter tasting compounds - denatonium benzoate, quinine hydrochloride, phenylthiourea, and the pungent constituent of chilli peppers - capsaicin). In addition, stomach irritants (copper chloride and copper sulphate), and a phosphodiesterase IV inhibitor also rapidly blocked movement. A concentration-dependant relationship was established for five of these compounds, showing potency of inhibition as capsaicin (IC(50) = 11.9±4.0 µM) > quinine hydrochloride (IC(50) = 44.3±6.8 µM) > denatonium benzoate (IC(50) = 129±4 µM) > phenylthiourea (IC(50) = 366±5 µM) > copper sulphate (IC(50) = 1433±3 µM). In contrast, 21 compounds within the cytotoxic and receptor agonist/antagonist classes did not affect cell behaviour. Further analysis of bitter and pungent compounds showed that the effect on cell behaviour was reversible and not cytotoxic, suggesting an uncharacterised molecular mechanism of action for these compounds. These results therefore demonstrate that Dictyostelium has potential as a non-sentient model in the analysis of the molecular effects of tastants, although it has limited utility in identification of emetic agents in general. Public Library of Science 2011-09-08 /pmc/articles/PMC3169598/ /pubmed/21931717 http://dx.doi.org/10.1371/journal.pone.0024439 Text en Robery et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Robery, Steven
Mukanowa, Janina
Percie du Sert, Nathalie
Andrews, Paul L. R.
Williams, Robin S. B.
Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
title Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
title_full Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
title_fullStr Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
title_full_unstemmed Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
title_short Investigating the Effect of Emetic Compounds on Chemotaxis in Dictyostelium Identifies a Non-Sentient Model for Bitter and Hot Tastant Research
title_sort investigating the effect of emetic compounds on chemotaxis in dictyostelium identifies a non-sentient model for bitter and hot tastant research
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169598/
https://www.ncbi.nlm.nih.gov/pubmed/21931717
http://dx.doi.org/10.1371/journal.pone.0024439
work_keys_str_mv AT roberysteven investigatingtheeffectofemeticcompoundsonchemotaxisindictyosteliumidentifiesanonsentientmodelforbitterandhottastantresearch
AT mukanowajanina investigatingtheeffectofemeticcompoundsonchemotaxisindictyosteliumidentifiesanonsentientmodelforbitterandhottastantresearch
AT perciedusertnathalie investigatingtheeffectofemeticcompoundsonchemotaxisindictyosteliumidentifiesanonsentientmodelforbitterandhottastantresearch
AT andrewspaullr investigatingtheeffectofemeticcompoundsonchemotaxisindictyosteliumidentifiesanonsentientmodelforbitterandhottastantresearch
AT williamsrobinsb investigatingtheeffectofemeticcompoundsonchemotaxisindictyosteliumidentifiesanonsentientmodelforbitterandhottastantresearch