INTRODUCTION: To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. METHODS: Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. RESULTS: Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. CONCLUSION: Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.
INTRODUCTION: To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. METHODS: Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. RESULTS: Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. CONCLUSION: Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.
Authors: Theodorus B M Hakvoort; Perry D Moerland; Raoul Frijters; Aleksandar Sokolović; Wilhelmina T Labruyère; Jacqueline L M Vermeulen; Emiel Ver Loren van Themaat; Timo M Breit; Floyd R A Wittink; Antoine H C van Kampen; Arthur J Verhoeven; Wouter H Lamers; Milka Sokolović Journal: J Biol Chem Date: 2011-03-10 Impact factor: 5.157
Authors: Raoul Frijters; Marianne van Vugt; Ruben Smeets; René van Schaik; Jacob de Vlieg; Wynand Alkema Journal: PLoS Comput Biol Date: 2010-09-23 Impact factor: 4.475
Authors: Wilco W M Fleuren; Stefan Verhoeven; Raoul Frijters; Bart Heupers; Jan Polman; René van Schaik; Jacob de Vlieg; Wynand Alkema Journal: Nucleic Acids Res Date: 2011-05-27 Impact factor: 16.971
Authors: Wilco Wm Fleuren; Erik Jm Toonen; Stefan Verhoeven; Raoul Frijters; Tim Hulsen; Ton Rullmann; René van Schaik; Jacob de Vlieg; Wynand Alkema Journal: BioData Min Date: 2013-02-04 Impact factor: 2.522
Authors: Raoul Frijters; Bart Heupers; Pieter van Beek; Maurice Bouwhuis; René van Schaik; Jacob de Vlieg; Jan Polman; Wynand Alkema Journal: Nucleic Acids Res Date: 2008-04-28 Impact factor: 16.971