Mechanistic Toxicogenomics

This is used to improve human risk assessment by expanding accessible interspecies biomarkers of toxicity and improving the understanding of interspecies similarities and differences. A case example was presented involving identification of gene expression alterations in the rat lens associated with formation of cataracts, following administration of a 5-lipoxygenase inhibitor. The pattern of gene expression confirmed that the compound inhibited the synthesis of cholesterol and that lens crystalline structural proteins were targets of drug cataractogenesis. Further studies are needed to investigate interspecies relevance of the mechanistic-based markers of the onset and progression of cataracts.

These examples provide evidence that toxicogenomics can assist with investigations of tox-icological mechanisms that involve generating and testing hypotheses, as well as identifying biomarkers useful for making interspecies predictions. However, it may not be appropriate for toxicogenomics to be used in a definitive manner at present to disprove hypotheses, confirm causality, predict safety, or replace any existing traditional safety assays. Definitive follow-up studies are needed to fully evaluate and confirm the mechanistic insights generated by toxicogenomics. Applications of the technology, formation of strategic partnerships, peer-reviewed publication of toxicogenomic data, and clarification of regulatory and industry uncertainties represent ways to advance the usefulness of toxicogenomic technology.

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