Enantioselective CYP inhibition by diclofop, the active metabolite of diclofop-methyl: Mechanism and relevance for human exposure.

Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evaluated the enantioselective inhibition by racemic DF and its enantiomers over the major cytochrome P450 (CYP) isoforms present in human liver microsomes. The inhibition screening showed that (+)-DF preferentially inhibited CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5, whereas (-)-DF was more active against CYP2C19 and CYP3A4/5. IC50 and kinetic studies confirmed moderate inhibition without time-dependent effect. DF competitively inhibited CYP2C9 with a Ki value of 2.2 µmol L-1. Finally, R1 factor estimations indicated that in vivo inhibition is unlikely even at exposure levels up to 100-fold above the acceptable daily intake. These results highlight the enantioselective inhibitory potential of a pesticide metabolite and its relevance for pesticide-drug interactions and human toxicity.