Qualitative and quantitative comparison of toxicological properties of racemates and their enantiomers with metabolomics

BASF’s Experimental Toxicology and Ecology unit and metanomics GmbH implemented a project to predict toxicological risks by measuring metabolite profiles in rat plasma from short-term repeated dose studies in rats. Metabolome analysis in plasma was performed after 7, 14 and 28 days and relative endogenous metabolite levels in treated rats versus controls were analyzed. Sets of common metabolite level changes were arranged to characterize several toxicological MOAs (so-called MOA patterns). A MetaMapTox databasewithmore than 500 reference compounds was developed. Some chemicals can be produced as mixtures or as pure enantiomers. The chiral properties of the molecules may have different effects on biological entities. The purpose of this studywas to compare toxicological properties of mixtures and their corresponding pure enantiomers regarding metabolite levels. Metabolome analysis of two different mixtures and their respective enantiomers indicated no biological relevant differences regarding thequalitative toxicity towards the assumed target organs as well as the quantitative amount of the toxicity, thereby confirming the toxicity equivalence of the enantiomers. The present results can be seen as proof of concept for the use of metabolomics concerning toxicological assessment of enantiomers. For complete evaluation, it will be interesting to test more enantiomers with different toxicological properties.