Toxicogenomics applied to predictive and exploratory toxicology for the safety assessment of new chemical entities: a long road with deep potholes.

摘要

Toxicology is the perturbation of metabolism by external factors such as xenobiotics, environmental factors or drugs. As such, toxicology covers a broad range of fields from studies of the whole organism responses to minute biochemical events. Mechanistic toxicogenomics is an attempt to harness genomic tools to understand the physiological basis for a toxic event based on an analysis of transcriptional, translational or metabolomic profiles. These studies are complicated by non-toxic adaptive responses in transcript, protein or metabolite expression levels that have to be distinguished from those that are proximally related to the toxic event. Substantial progress has been made on the identification of biomarkers and the establishment of screens derived from such toxicogenomics studies. The ultimate goal, of course, is predictive toxicogenomics, which is an attempt to infer the likelihood of occurrence of a toxic event with exposure to a new agent based upon comparative responses with large databases of gene, protein or metabolite expression data. Gene expression databases are currently limited by the fact that measurable toxic phenotypes generally precede or at best coincide with the earliest observable changes in transcriptional profiles. Unfortunately, predictive protein databases have been limited by technical difficulties. Metabonomics-based databases, which would probably have the highest predictive value, are limited in turn by the inability to perform high dose studies in humans. This chapter will conclude by reviewing those elements of toxicogenomics that apply specifically to the development of anti-infectives and the potential for accurately modelling the toxicity of future drugs.