Development of a test battery for the detection of induction of molecular initiating events of cholestatic liver toxicity induced by chemical compounds

Julen Sanz-Serrano, Emilio Benfenati, Annika Hanna Drees, Domenico Gadaleta, Marina Garcia de Lomana, René Geci, Rafael Gozalbes, Nynke Kramer, Amy Maerten, Rita Ortega, Alicia Paini, Susana Proença, Eva Serrano-Candelas, Anouk Verhoeven, Mathieu Vinken

Onderzoeksoutput: Poster

Samenvatting

Liver toxicity induced by chemical compounds associated with the accumulation of noxious bile acids or so-called cholestasis remains a challenge to predict. The present case study aimed to tackle this issue by developing a set-up relying on a combination of in vitro, in silico and kinetic modelling. The in vitro modelling was focused on detecting molecular initiating events (MIEs), in particular changes in transporter functionality and expression as well as in bile canaliculi dynamics, in the adverse outcome pathway (AOP) mechanistically describing cholestatic liver injury. The in silico modelling comprised a series of quantitative structure-activity relationship (QSAR) models to predict inhibitory/substrate effects on transporters. Prediction of systemic availability was done by means of a high-throughput physiologically-based kinetic (HT-PBK) modelling approach. Throughout the case study, focus was put on 7 chemicals, among which 5 included in the epaa NAM Designathon reference list. The combined outcome from the in vitro, in silico and kinetic modelling exercises allowed classification of the chemicals according to the level of cholestatic liver toxicity concern.
Originele taal-2English
StatusUnpublished - 24 mrt 2024
Evenement3rd Annual ONTOX Meeting - Utrecht, Netherlands
Duur: 24 apr 202425 apr 2024

Conference

Conference3rd Annual ONTOX Meeting
Verkorte titelONTOX AM 2024
Land/RegioNetherlands
StadUtrecht
Periode24/04/2425/04/24

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