title: Assessment of the inhibitory effects of pyrethroids against human carboxylesterases.
abstract: Pyrethroids are broad-spectrum insecticides that widely used in many countries, while humans may be exposed to these toxins by drinking or eating pesticide-contaminated foods. This study aimed to investigate the inhibitory effects of six commonly used pyrethroids against two major human carboxylesterases (CES) including CES1 and CES2. Three optical probe substrates for CES1 (DME, BMBT and DMCB) and a fluorescent probe substrate for CES2 (DDAB) were used to characterize the inhibitory effects of these pyrethroids. The results demonstrated that most of the tested pyrethroids showed moderate to weak inhibitory effects against both CES1 and CES2, but deltamethrin displayed strong inhibition towards CES1. The IC50values of deltamethrin against CES1-mediated BMBT, DME, and DMCB hydrolysis were determined as 1.58μM, 2.39μM, and 3.3μM, respectively. Moreover, deltamethrin was cell membrane permeable and capable of inhibition endogenous CES1 in living cells. Further investigation revealed that deltamethrin inhibited CES1-mediated BMBT hydrolysis via competitive manner but noncompetitively inhibited DME or DMCB hydrolysis. The inhibition behaviors of deltamethrin against CES1 were also studied by molecular docking simulation. The results demonstrated that CES1 had at least two different ligand-binding sites, one was the DME site and another was the BMBT site which was identical to the binding site of deltamethrin. In summary, deltamethrin was a strong reversible inhibitor against CES1 and it could tightly bind on CES1 at the same ligand-binding site as BMBT. These findings are helpful for the deep understanding of the interactions between xenobiotics and CES1.
authors.affiliation: The Second Affiliated Hospital of Dalian Medical University, Dalian 110623, China; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lei
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Tong-Yi
authors.initials: TY
authors.lastname: Dou
authors.affiliation: Dalian Medical University, Dalian 116044, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Feng
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Yin
authors.affiliation: Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Luo
authors.affiliation: The Second Affiliated Hospital of Dalian Medical University, Dalian 110623, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: geguangbo@dicp.ac.cn.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007306:Insecticides / Q000378:metabolism* / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011722:Pyrethrins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human
keywords: Deltamethrin; Human carboxylesterase 1; Ligand-binding sites; Pyrethroids