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Modeling Biotransformation Using In Vitro Data on Parent-Metabolite Pairs within the ToxCast Phase I Chemical Set
Citation:
MARTIN, M. T., D. J. DIX, K. A. HOUCK, R. JUDSON, AND R. J. KAVLOCK. Modeling Biotransformation Using In Vitro Data on Parent-Metabolite Pairs within the ToxCast Phase I Chemical Set. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
However, comparable responses were not seen when parent and metabolite cytotoxicities were evaluated independently. In some cases, biochemical assay results for explicit metabolites also yielded distinct activities relative to the parent chemical, emphasizing the need for development of biochemical assays with biotransformation capacity or to account for biotransformation through other approaches. These approaches may include metabolic simulation or prediction along with targeted testing of metabolites. The results from the spectrum of assays with and without metabolic capacity are being incorporated into the data mining and analysis process. The bioactivity profiles of parent-metabolite pairs allowed us to identify assays with the potential to recognize chemical-specific biostransformation. This will be evaluated further by the selection of assays, and parent and metabolite chemicals for Phase II of ToxCast.
Description:
A major focus in toxicology research is the development of new in vitro methods to predict in vivo chemical toxicity. Within the EPA ToxCast program, a broad range of in vitro biochemical and cellular assays have been deployed to profile the biological activity of 320 Phase I chemicals. Only a limited number of these assays have metabolic capacity, and it is not feasible to test all potential metabolites in the over 600 assays of ToxCast. ToxCast Phase I chemicals include 12 parent-metabolite pairs of chemicals, creating the possibility to compare in vitro assay results between the parent and metabolite. Clear differences in cytotoxicity across several cell lines were observed when comparing parent and metabolite ToxCast results. Parent chemicals tested in cell-based systems with metabolic capacity, demonstrated differential cytotoxicity under differing assay metabolic conditions.