ChOLLATERAL · Generation of an adverse outcome pathway network on cholestatic liver injury for mechanism-based in vitro testing of chemicals.

Generation of an adverse outcome pathway network on cholestatic liver injury for mechanism-based in vitro testing of chemicals.

Cholestasis refers to toxic bile acid accumulation that mainly occurs in the liver and can be induced by many chemical compounds, in particular drugs. At present, drug-induced cholestatic injury (DICI) is difficult to predict and is a prominent cause of drug withdrawal from the market. Cholestasis is of high clinical concern and, therefore, represents a significant economic and societal burden. A solution lies in better understanding the mechanisms of DICI. A pragmatic tool to capture the mechanistic basis of toxic effects is the adverse outcome pathway (AOP, Figure 1), which is a schematic representation of the sequence of events that lead to an adverse outcome. Current AOP constructs frequently provide an oversimplified reflection of the mechanisms underlying toxicity by underestimating initiating events and biological responses. The overall objective of this project was to elucidate the molecular mechanisms of cholestatic liver injury based on in vitro experimentation and re-use of in vivo and clinical samples, to reliably predict the cholestatic potential of chemicals. In particular, 2 specific research objectives were outlined: 1. To establish a quantitative representation (AOP network) describing the mechanisms of human DICI by considering multiple molecular initiating events and key events of both adversity and homeostatic adaptation. 2. To accurately establish the human cholestatic potential of new chemical entities, such as cosmetic ingredients, biocides, food additives and nanoparticles, using an in vitro 3D liver spheroid model and a battery of tests mechanistically anchored in the novel AOP network. This multidisciplinary project addresses a ubiquitous medical need regarding the prediction of cholestatic liver toxicity, and may serve as a generic prototype to reliably predict other types of chemical-induced toxicity based on mechanistic knowledge, avoiding the use of animals. Such human-based, animal-saving, approaches to assess the safety of chemicals are urgently needed because of scientific and ethical reasons. By improving in vitro predictability of DICI, the results of this project aim to contribute towards decreased pre- and post-marketing drug failure, and lessening the clinical burden, with concomitant positive effects at the economical level.

Data: CORDIS, © European Union