The liver pharmacological and xenobiotic gene response repertoire

Abstract

We have used a supervised classification approach to systematically mine a large microarray database derived from livers of compound-treated rats. Thirty-four distinct signatures (classifiers) for pharmacological and toxicological end points can be identified. Just 200 genes are sufficient to classify these end points. Signatures were enriched in xenobiotic and immune response genes and contain un-annotated genes, indicating that not all key genes in the liver xenobiotic responses have been characterized. Many signatures with equal classification capabilities but with no gene in common can be derived for the same phenotypic end point. The analysis of the union of all genes present in these signatures can reveal the underlying biology of that end point as illustrated here using liver fibrosis signatures. Our approach using the whole genome and a diverse set of compounds allows a comprehensive view of most pharmacological and toxicological questions and is applicable to other situations such as disease and development.

Demonstration Study: A Protocol to Combine Online Tools and Databases for Identifying Potentially Repurposable Drugs

“…A study titled "Drug Matrix In Vitro Toxicogenomic Study-Rat Hepatocytes [Affymetrix]" [12,13] was selected for further analysis. Although drug-treatment studies performed on normal human cell lines would be preferred for repurposed disease prediction, for this query, all human studies were only carried out for cancer cell lines or virus-infected cells.…”

On how to solve large-scale log-determinant optimization problems

“…We aim to estimate the covariance matrix of a Gaussian graphic model whose conditional independence is unknown. Another gene set is the Iconix microarray data obtained from 255 drug-treated rat livers; see Natsoulis et al [23] for details. For both data sets, although our method can handle problems with larger matrix dimensions, we test only on a subset of the data.…”

Toxicogenomics Investigation Under the eTOX Project

“…The DrugMatrix database, established by Iconix Biosciences and recently acquired by the National Toxicology Program, consists of gene expression responses in several tissues including liver, kidney, heart and primary hepatocytes of male Sprague-Dawley rats for over 630 known drugs and toxicants ingested at two or more doses and measured at different time points in triplicate [8,9]. Histopathology, blood chemistry and hematology data are also included with the gene expression data, allowing investigating the relation between the gene expression differentiations and the pathology.…”