Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling.
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.
a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands.
Isoude A
IA
Kuijper
a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands.
Huan
H
Yang
a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands.
Bob
B
Van De Water
a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands.
Joost B
JB
Beltman
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000517:prevention & control; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008962:Models, Theoretical; D018384:Oxidative Stress / Q000187:drug effects; D058767:Protein Unfolding; D013312:Stress, Physiological / Q000187:drug effects
Drug induced liver injury (DILI); adverse outcome pathway; cell fate; death pathway; dynamical modeling; ordinary differential equations; predictive toxicology; stress pathway