title: The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.
abstract: 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.
authors.affiliation: *Laboratoire d'Ecologie Alpine (LECA), UMR 5553 CNRS, Université de Grenoble, Grenoble 38041, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Chandor-Proust
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bibby
authors.forename: Myriam
authors.initials: M
authors.lastname: Régent-Kloeckner
authors.forename: Jessica
authors.initials: J
authors.lastname: Roux
authors.forename: Emilie
authors.initials: E
authors.lastname: Guittard-Crilat
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Poupardin
authors.forename: Muhammad Asam
authors.initials: MA
authors.lastname: Riaz
authors.forename: Mark
authors.initials: M
authors.lastname: Paine
authors.forename: Chantal
authors.initials: C
authors.lastname: Dauphin-Villemant
authors.forename: Stéphane
authors.initials: S
authors.lastname: Reynaud
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: David
mesh_terms: D000330:Aedes / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000201:enzymology; D001547:Benzaldehydes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005818:Genetic Engineering; D008658:Inactivation, Metabolic; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007303:Insect Vectors / Q000187:drug effects* / Q000201:enzymology; D007305:Insecticide Resistance / Q000187:drug effects / Q000235:genetics; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011722:Pyrethrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics
chemical_list: D001547:Benzaldehydes; D001565:Benzoates; D019476:Insect Proteins; D007306:Insecticides; D007527:Isoenzymes; D011722:Pyrethrins; C064808:3-phenoxybenzaldehyde; C017618:3-phenoxybenzoic acid; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase