Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

Abstract

We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of “toxicity pathways” is described in the context of the 2007 US National Academies of Science report, “Toxicity testing in the 21st Century: A Vision and A Strategy.” Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity) – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular “virtual tissue” model of the liver lobule that combines molecular circuits in individual hepatocytes with cell–cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the aryl hydrocarbon receptor toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsym™) to understand drug-induced liver injury (DILI), the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments

“…Meeting them is outside the scope of systems biology models currently in use to predict APAP hepatotoxicity [20, 21]. We use the virtual experiment approach described by Kirschner et al [17] along with the enhanced strategies detailed by Petersen et al [22, 23].…”

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

“…DILIsym has been described previously (Bhattacharya et al , 2012; Shoda et al , 2014; Woodhead et al , 2012). Briefly, DILIsym is a multi-scale and “middle-out” platform focused on the liver as the primary organ of interest, which includes detailed liver cellular dynamics and biochemistry, extends to whole body drug distribution and systemic circulation of mediators and biomarkers, and accounts for inter-individual differences through variation in anthropometrics and biochemistry.…”

Strategies for Minimisation of the Cholestatic Liver Injury Liability Posed by Drug-Induced Bile Salt Export Pump (BSEP) Inhibition

“…Kenna et al most notably via reactive metabolite formation (e.g., [114,115]), and may offer an opportunity to address some of these questions and improve the prediction of DILI potential caused by BSEP inhibition. The ITC has highlighted BSEP as one of the emerging transporters that needs to be considered when evaluating drug safety.…”