Toxicogenomics in Drug Development

Abstract

Toxicogenomics represents the merging of toxicology with technologies that have been developed, together with bioinformatics, to identify and quantify global gene expression changes. It represents a new paradigm in drug development and risk assessment, which promises to generate a wealth of information towards an increased understanding of the molecular mechanisms that lead to drug toxicity and efficacy, and of DNA polymorphisms responsible for individual susceptibility to toxicity. Gene expression profiling, through the use of DNA microarray and proteomic technologies will aid in establishing links between expression profiles, mode of action and traditional toxic endpoints. Such patterns of gene expression, or 'molecular fingerprints' could be used as diagnostic or predictive markers of exposure, that is characteristic of a specific mechanism of induction of that toxic or efficacious effect. It is anticipated that toxicogenomics will be increasingly integrated into all phases of the drug development process particularly in mechanistic and predictive toxicology, and biomarker discovery. This review provides an overview of the expression profiling technologies applied in toxicogenomics, and discusses the promises as well as the future challenges of applying this discipline to the drug development process.Keywords. DNA microarrays; PCR; bioinformatics; gene expression profiling; genomics; proteomics; biomarkers; toxicology. INTRODUCTIONThe evolution of new innovative technologies in parallel with recent dramatic increases in genomic knowledge is anticipated to revolutionize toxicological studies by providing significant advances in the understanding and prediction of the toxicity and efficacy of new drugs (38, 39, 52). In classic toxicology, potential adverse effects resulting from drug exposure are evaluated using endpoints such as body and organ weight changes, biochemical and histopathological observations. Such observations, however, do not provide information about a drug's mode of action. To better evaluate the adverse effects associated with drug exposure, one needs to understand the drug's specific mode of action. Drugs are expected to induce a multitude of complex molecular perturbations in a wide variety of pathways, involving differential gene expression at the transcript and functional protein level, leading to efficacious and/or pathological outcomes. These changes in gene expression are often more sensitive and characteristic of the toxic response or process than currently employed endpoints of pathology, and have the potential to indicate toxicity already at lower doses or at earlier time points.Technological advances derived from genomic research have made it possible to follow transcriptional and translational events of genes and even the entire genome. The application of genome-wide expression profiling technologies to toxicology has created a new subdiscipline coined 'toxicogenomics,' which has the potential to provide a more comprehensive understanding of the mechanisms of pharmacology ...

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