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Genome Inform. 2006;17(2):77-88.

Development of an approach for ab initio estimation of compound-induced liver injury based on global gene transcriptional profiles.

Author information

  • 1Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle, WA 98109, USA. xudong_dai@merck.com

Abstract

Toxicity is a major cause of failure in drug development. A toxicogenomic approach may provide a powerful tool for better assessing the potential toxicity of drug candidates. Several approaches have been reported for predicting hepatotoxicity based on reference compounds with well-studied toxicity mechanisms. We developed a new approach for assessing compound-induced liver injury without prior knowledge of a compound's mechanism of toxicity. Using samples from rodents treated with 49 known liver toxins and 10 compounds without known liver toxicity, we derived a hepatotoxicity score as a single quantitative measurement for assessing the degree of induced liver damage. Combining the sensitivity of the hepatotoxicity score and the power of a machine learning algorithm, we then built a model to predict compound-induced liver injury based on 212 expression profiles. As estimated in an independent data set of 54 expression profiles, the built model predicted compound-induced liver damage with 90.9% sensitivity and 88.4% specificity. Our findings illustrate the feasibility of ab initio estimation of liver toxicity based on transcriptional profiles.

PMID:
17503381
[PubMed - indexed for MEDLINE]
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