Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches

Sudin Bhattacharya, Lisl K M Shoda, Qiang Zhang, Courtney G. Woods, Brett A. Howell, Scott Q. Siler, Jeffrey L. Woodhead, Yuching Yang, Patrick McMullen, Paul B. Watkins, E. Andersen Melvin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numberArticle 462
JournalFrontiers in Physiology
Volume3 DEC
DOIs
StatePublished - 2012
Externally publishedYes

Profile

Systems Biology
Drug Design
Liver
Drug-Induced Liver Injury
Chemical Safety
Aryl Hydrocarbon Receptors
Gene Regulatory Networks
Environmental Exposure
Acetaminophen
Biological Processes
Computational Biology
Drug-Related Side Effects and Adverse Reactions
Cell Communication
Hepatocytes
Cell Count
Genome
Gene Expression
DNA
Proteins

Keywords

  • Chemical toxicity
  • Computational toxicology
  • Drug toxicity
  • Multi-scale modeling
  • Systems toxicology
  • Toxicity pathways
  • Virtual liver

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Bhattacharya, S., Shoda, L. K. M., Zhang, Q., Woods, C. G., Howell, B. A., Siler, S. Q., ... Melvin, E. A. (2012). Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches. Frontiers in Physiology, 3 DEC, [Article 462]. DOI: 10.3389/fphys.2012.00462

Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches. / Bhattacharya, Sudin; Shoda, Lisl K M; Zhang, Qiang; Woods, Courtney G.; Howell, Brett A.; Siler, Scott Q.; Woodhead, Jeffrey L.; Yang, Yuching; McMullen, Patrick; Watkins, Paul B.; Melvin, E. Andersen.

In: Frontiers in Physiology, Vol. 3 DEC, Article 462, 2012.

Research output: Contribution to journalArticle

Bhattacharya, S, Shoda, LKM, Zhang, Q, Woods, CG, Howell, BA, Siler, SQ, Woodhead, JL, Yang, Y, McMullen, P, Watkins, PB & Melvin, EA 2012, 'Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches' Frontiers in Physiology, vol 3 DEC, Article 462. DOI: 10.3389/fphys.2012.00462
Bhattacharya S, Shoda LKM, Zhang Q, Woods CG, Howell BA, Siler SQ et al. Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches. Frontiers in Physiology. 2012;3 DEC. Article 462. Available from, DOI: 10.3389/fphys.2012.00462

Bhattacharya, Sudin; Shoda, Lisl K M; Zhang, Qiang; Woods, Courtney G.; Howell, Brett A.; Siler, Scott Q.; Woodhead, Jeffrey L.; Yang, Yuching; McMullen, Patrick; Watkins, Paul B.; Melvin, E. Andersen / Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches.

In: Frontiers in Physiology, Vol. 3 DEC, Article 462, 2012.

Research output: Contribution to journalArticle

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