Computational study on the detoxifying mechanism of DDT metabolized by cytochrome P450 enzymes

Highlights: • The detoxifying mechanism and derivatives of DDT were revealed by MD, QM/MM and DFT approaches. • The reactivity of the electrophilic addition and the hydrogen abstraction were compared. • The main derivatives are epoxides (2,3-oxide-DDT and 3,4-oxide-DDT), DDE and dicofol. • By ecotoxicity assessment calculation, the derivatives are toxic to aquatic organisms. Predicting the detoxifying mechanism and potential toxic derivatives of xenobiotic substances is significant for risk assessment. The present study delineated the detoxifying mechanism of 1-chloro-4-[2,2,2-trichloro-1-(4-chlorophenyl)ethyl]benzene (DDT) metabolized by human P450 enzymes using a combination of molecular dynamic (MD), quantum mechanics/molecular mechanics (QM/MM) and density functional theory (DFT). This study highlights that DDT can be metabolized by P450 enzymes through the hydrogen abstraction and electrophilic addition mechanism, and the main derivatives are epoxides (2,3-oxide-DDT and 3,4-oxide-DDT), DDE and dicofol. The epoxides are unstable and the C-O bond cleavage easily occurs by the reaction with hydronium ion or hydroxyl radicals, yielding endocrine disruptor hydroxylated DDT. The eco-toxicity evaluation indicates that the derivatives of DDT are less toxic than DDT, and the solubility increase of the derivatives can accelerate their excretion from the body. The study can provide an understanding of the biotransformation of DDT by the P450 enzymes in human livers.