Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

ABSTRACT

Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI.

Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver.

Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs.

KEYWORDS:

• Drug induced liver injury (DILI)
• dynamical modeling
• ordinary differential equations
• stress pathway
• death pathway
• predictive toxicology
• cell fate
• adverse outcome pathway

Article highlights

• Current techniques to predict DILI are insufficient, leading to health risks and financial losses.

• Dynamical modeling can give insights into mechanism, behaviour of a stress (death) pathway and its relation to adverse effects.

• In the last decade, enormous progress has been made in developing dynamical models for stress and (death) pathways.

• Combining high content in vitro experiments with dynamical modeling could lead to better techniques to detect adverse effects of drugs.

This box summarizes key points contained in the article.

Acknowledgements

We would like to thank Suzanna Huppelschoten, Steven Hiemstra and Luc Bischoff for insightful discussions and Frederic Bois for his useful comments on a previous version of the manuscript.

Declaration of interest

This will include all details of conflict of interest, consultancies, honoraria, advisory board participation. The usual blurb will go after any declaration details The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO, InnoSysTox, number 40-42600-98-14016, to B van de Water and JB Beltman) and from the European Research Council (ERC, EUToxRisk21, number 681002, to to B van de Water and JB Beltman).