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A combined in vitro/in silico approach to identifying off-target receptor toxicity

leedale, J, Sharkey, K, Colley, H, Norton, A, Peeney, D, Mason, C, Sathish, J, Murdoch, C, Sharma, P and Webb, SD (2018) A combined in vitro/in silico approach to identifying off-target receptor toxicity. iScience, 4. pp. 84-96. ISSN 2589-0042

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Abstract

Many xenobiotics can bind to off-target receptors and cause toxicity via the dysregulation of downstream transcription factors. Identification of subsequent off-target toxicity in these chemicals has often required extensive chemical testing in animal models. An alternative, integrated in vitro/in silico approach for predicting toxic off-target functional responses is presented to refine in vitro receptor identification and reduce the burden on in vivo testing. As part of the methodology, mathematical modelling is used to mechanistically describe processes that regulate transcriptional activity following receptor-ligand binding informed by transcription factor signalling assays. Critical reactions in the signalling cascade are identified to highlight potential perturbation points in the biochemical network that can guide and optimise additional in vitro testing. A physiologically-based pharmacokinetic model provides information on the timing and localisation of different levels of receptor activation informing whole-body toxic potential resulting from off-target binding.

Item Type: Article
Subjects: Q Science > QA Mathematics
Q Science > QD Chemistry
Divisions: Applied Mathematics
Publisher: Cell Press
Date Deposited: 24 May 2018 09:42
Last Modified: 14 Jun 2018 10:31
DOI or Identification number: 10.1016/j.isci.2018.05.012
URI: http://researchonline.ljmu.ac.uk/id/eprint/8706

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