The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling
Autor(es): Chandor-Proust Alexia,Bibby Jaclyn,Régent-Kloeckner Myriam,Roux Jessica,Guittard-Crilat Emilie,Poupardin Rodolphe,Riaz Muhammad Asam,Paine Mark,Dauphin-Villemant Chantal,Reynaud Stéphane,David Jean-Philippe
Resumo: The resistance of mosquitoes to chemical insecticides is threatening vector control programmes worldwide. Cytochrome P450 monooxygenases (CYPs) are known to play a major role in insecticide resistance, allowing resistant insects to metabolize insecticides at a higher rate. Among them, members of the mosquito CYP6Z subfamily, like Aedes aegypti CYP6Z8 and its Anopheles gambiae orthologue CYP6Z2, have been frequently associated with pyrethroid resistance. However, their role in the pyrethroid degradation pathway remains unclear. In the present study, we created a genetically modified yeast strain overexpressing Ae. aegypti cytochrome P450 reductase and CYP6Z8, thereby producing the first mosquito P450-CPR (NADPH-cytochrome P450-reductase) complex in a yeast recombinant system. The results of the present study show that: (i) CYP6Z8 metabolizes PBAlc (3-phenoxybenzoic alcohol) and PBAld (3-phenoxybenzaldehyde), common pyrethroid metabolites produced by carboxylesterases, producing PBA (3-phenoxybenzoic acid); (ii) CYP6Z8 transcription is induced by PBAlc, PBAld and PBA; (iii) An. gambiae CYP6Z2 metabolizes PBAlc and PBAld in the same way; (iv) PBA is the major metabolite produced in vivo and is excreted without further modification; and (v) in silico modelling of substrate-enzyme interactions supports a similar role of other mosquito CYP6Zs in pyrethroid degradation. By playing a pivotal role in the degradation of pyrethroid insecticides, mosquito CYP6Zs thus represent good targets for mosquito-resistance management strategies.
Palavras-Chave: Cytochrome P450 monooxygenase; Insecticide; Metabolism; Mosquito; Pyrethroid; Recombinant system; Resistance
Imprenta: The Biochemical Journal, v. 455, n. 1, p. 75-85, 2013
Identificador do objeto digital: 10.1042/BJ20130577
Descritores: Aedes aegypti - Pathogenesis ; Aedes aegypti - Proteins ; Aedes aegypti - Public health
Data de publicação: 2013
