Abstract
Metabolically active compounds can cause toxicity which would otherwise be undetected using traditional in vitro assays with limited proficiency for xenobiotic metabolism. Introduction of liver microsomes to assay systems enables enhanced identification of compounds that require biotransformation to induce toxicity. Previously, metabolically active compounds from the Tox21 10 K compound library were identified using assays probing two targets, p53 and acetylcholinesterase (AChE), in the presence and absence of human or rat liver microsomes, due to the established roles of cytochrome P450 (CYP) enzymes in human drug metabolism. To further explore the role of metabolic activation, the activities of the identified metabolically active compounds were evaluated against five CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP bioactivities were found to be highly predictive (>80 % accuracy) of compounds that required metabolic activation in these assays. Chemical features significantly enriched in metabolically active compounds, as well as chemical features that were specific for each of the five CYPs, were identified. Product use exposures of the metabolically active compounds were examined in this study, with "pesticides" appearing to be the largest category that may produce harmful metabolites. Additionally, the compound interactions with different CYPs were assessed and frequencies for both classes of compounds, drugs and environmental chemicals, were found to be proportionally similar across the five CYP isoforms.