[DOT 2019] Improving Valvulopathy Prediction by Qualifying 5-HT2B Functional Assay Technologies

[DOT 2019] Improving Valvulopathy Prediction by Qualifying 5-HT2B Functional Assay Technologies
File Name/Number:
DOT 2019

Year:
2019

Valvulopathy is one of the most dramatic side effects appearing upon chronic use of some 5-HT2B agonists. Stimulation of Valvular Interstitial Cells with some 5HT2B agonists induces an abnormal proliferation of those cells while other agonists do not produce such effect. A recent paper from Papoian T et al. (Toxicol Pathol 2017; 45:381-388), presented at the 2018 SPS meeting, suggested that monitoring stimulation of mitogen activated protein kinase (MAPK)
pathway was a better predictor of valvulopathy occurrence than the other three classical readouts (IP accumulation, calcium release, and beta-arrestin translocation). Eurofins Discovery set up an assay that follows MAPK activation and ERK phosphorylation upon 5-HT2B receptor stimulation using the same cell line in which IP1 accumulation is already monitored. Both assays use the same recombinant cell line and fluorescence transfer (HTRF®) as a detection method making the comparison of compounds effects more relevant. We compared the data obtained with the two readouts for various 5-HT2B agonists, valvulopathogens or not (norfenfluramine, cabergoline, benfluorex, etc.). Results are presented here. They do not suggest a significant advantage for the MAPK readout for prediction. Analysis on a larger panel of compounds may be required or the previously observed differences may be linked to the differences in cellular models rather than the readout itself.