Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data

Citation

Purpose

  • Developing chemical in vitro-in vivo correlations (IVIVCs) between ARE pathway activation and hepatotoxicity.

Problem

  • In vitro assays have been used as an alternative to evaluate hepatotoxicity. However, the combination of in vitro and in vivo evaluations have not successfully replaced in vivo hepatotoxicity models.

Assumptions

  • The QSAR model based on the qHTS ARE-bla data sets can be used to predict the ARE activation when ARE experimental result is not available.
  • The active responses obtained from the biological response profiling can suggest potential hepatotoxicity.

Information

  • qHTS ARE-bla data set, In vivo hepatotoxicity data set, qHTS assay to identify small-molecule antagonists of the TR signaling pathway, qHTS assay to identify small-molecule agonists of the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway, and qHTS for inhibitors of TDP1.

Concepts

  • QSAR (quantitative structure activity relationship) models are regression or classification models used in the chemical and biological sciences and engineering, which relate a set of predictor variables to a response variable.
  • PCA (principal component analysis) is a statistical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables into a set of values of linearly uncorrelated variables called principal components.
  • AOP (adverse outcome pathways) is a logical sequence of biological responses that is useful for understanding complex toxicity phenomena.

Inferences

  • ARE activation can be predicted by QSAR model based on qHTS ARE-bla data sets.
  • Prediction of compounds outside the applicability domain is not as accurate as compounds within applicability domain.

Point of view

  • Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources.

Implications

  • The QSAR model based on the qHTS ARE-bla dataset can be applied to other biological assays.
  • The workflow that identified assays from a public big data source can be used to evaluate liver damage caused by oxidative stress.

-- HuanJin - 31 Mar 2017
Topic revision: r1 - 31 Mar 2017, HuanJin
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