Brief abstract
Many current medicines taste bitter, leading to low patient compliance and reduced therapeutic efficacy. Assessment of bitter taste effects of new medicines employs animal in vivo experiments that are time consuming and have limited throughput. We have investigated the replacement of animals in these tests with the amoeba Dictyostelium discoideum to show that cell behaviour is sensitive to bitter tasting compounds. Analysing of a range of structurally distinct bitter tastants using Dictyostelium, and comparing effects with responses in animal and human tests, suggests that Dictyostelium provides a useful replacement model for the prediction of bitter taste effects of new medicines.
Full abstract
A large number of therapeutically active compounds have a bitter taste. This often causes an aversive reaction - particularly in children - leading to decreased patient compliance and in some cases to severe reactions such as, nausea and vomiting. Identification of bitter taste liability during drug discovery utilises the rat in vivo brief access taste aversion (BATA) test which is time consuming and has limited throughput. Here, we investigate the suitability of using a simple non-animal model, the amoeba Dictyostelium discoideum, to examine taste-related responses and particularly to identify those molecules with a bitter taste liability. We initially analysed the acute effects of taste-related compounds on Dictyostelium cell behaviour to show no response to salty or sour conditions, or umami and sweet tasting compounds, whereas cells rapidly responded to bitter tastants. We then developed a medium-throughput assay, based in Dictyostelium, to monitor responses to a wide range of structurally diverse bitter tastants and a panel of blinded molecules. This assay employed visualising cells pre- and post-bitter tastant exposure, recording cell response with time-lapse photography and using computer-generated quantification to monitor changes in cell membrane movement. Dictyostelium showed varying responses to the bitter tastants, with IC50 values providing a rank order of potency. Comparison of Dictyostelium IC50 values to responses observed at a similar concentration range in the rat BATA test showed a significant positive correlation between the two models (p = 0.0172). In addition, the data showed a similar response of Dictyostelium to that provided by a human sensory panel assessment test. These experiments suggest that Dictyostelium may provide a suitable model for early prediction of bitterness for novel tastants and drugs, where a common response to bitter tastants appears to be conserved from a single-celled amoebae to humans.