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Understanding P450‐mediated Bio‐transformations into Epoxide and Phenolic Metabolites
Author(s) -
Tomberg Anna,
Pottel Joshua,
Liu Zhaomin,
Labute Paul,
Moitessier Nicolas
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201506131
Subject(s) - chemistry , cytochrome p450 , enzyme , drug metabolism , drug , epoxide , reactive intermediate , toxicity , biotransformation , metabolism , biochemistry , molecule , hydroxylation , stereochemistry , combinatorial chemistry , pharmacology , organic chemistry , biology , catalysis
Adverse drug reactions are commonly the result of cytochrome P450 enzymes (CYPs) converting the drugs into reactive metabolites. Thus, information about the CYP bioactivation of drugs would not only provide insight into metabolic stability, but also into the potential toxicity. For example, oxidation of phenyl rings may lead to either toxic epoxides or safer phenols. Herein, we demonstrate that the potential to form reactive metabolites is encoded primarily in the properties of the molecule to be oxidized. While the enzyme positions the molecule inside the binding pocket (selects the site of metabolism), the subsequent reaction is only dependent on the substrate itself. To test this hypothesis, we used this observation as a predictor of drug inherent toxicity. This approach was used to successfully identify the formation of reactive metabolites in over 100 drug molecules. These results provide a new perspective on the impact of functional groups on aromatic oxidation of drugs and their effects on toxicity.