Assessment of the inhibitory activity of the pyrethroid pesticide deltamethrin against human placental glutathione transferase P1-1: A combined kinetic and docking study.

Deltamethrin (DEL), which is a synthetic pyrethroid insecticide, has been used successfully all over the world to treat mosquito nets for the control of malaria. Glutathione S-transferases (GSTs; EC 2.5.1.18) catalyze the conjugation of reduced glutathione (GSH) to a variety of xenobiotics and are normally recognized as detoxification enzymes. Here, we used a colorimetric assay based on the human placental GSTP1-1 (hpGSTP1-1)-catalyzed reaction between GSH and the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) as well as molecular docking to investigate the mechanistic and structural aspects of hpGSTP1-1 inhibition by DEL. We show that DEL is a potent, noncompetitive inhibitor of hpGSTP1-1 with an IC ₅₀ value of 6.1 μM and K _i values of 5.61 ± 0.32 μM and 7.96 ± 0.97 μM at fixed [CDNB]-varied [GSH] and fixed [GSH]-varied [CDNB], respectively. DEL appears to be accommodated well in an eccentric cavity located at the interface of the hpGSTP1-1 homodimer, presumably causing conformational changes to the enzyme's substrate-binding sites such that the enzyme is no longer able to transform GSH and CDNB effectively. Correspondingly, considerable maternal exposure to and subsequent accumulation of DEL may interfere with the proper development of the vulnerable fetus, possibly increasing the risk of developing congenital defects.
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