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

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...

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Vydáno v:	Expert opinion on drug metabolism & toxicology Ročník 13; číslo 1; s. 5 - 17
Hlavní autoři:	Kuijper, Isoude A., Yang, Huan, Van De Water, Bob, Beltman, Joost B.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Taylor & Francis 02.01.2017
Témata:	adverse outcome pathway Animals cell fate Chemical and Drug Induced Liver Injury - diagnosis Chemical and Drug Induced Liver Injury - etiology Chemical and Drug Induced Liver Injury - prevention & control death pathway Drug Design Drug induced liver injury (DILI) Drug-Related Side Effects and Adverse Reactions - diagnosis Drug-Related Side Effects and Adverse Reactions - prevention & control dynamical modeling Humans Liver - drug effects Liver - pathology Models, Theoretical ordinary differential equations Oxidative Stress - drug effects predictive toxicology Protein Unfolding stress pathway Stress, Physiological - drug effects ordinary differential equations death pathway stress pathway cell fate predictive toxicology Drug induced liver injury (DILI) adverse outcome pathway dynamical modeling
ISSN:	1742-5255, 1744-7607
On-line přístup:	Získat plný text
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1
ISSN:	1742-5255 1744-7607
DOI:	10.1080/17425255.2017.1234607