title: Insecticide detoxification indicator strains as tools for enhancing chemical discovery screens.
abstract: BACKGROUND
  Insecticide discovery screens carried out on whole organisms screen for potency resulting from chemical activity at the target site. However, many potentially insecticidal compounds are naturally detoxified in vivo and do not make it to the target site. It is hypothesised that insect strains with their xenobiotic detoxification machinery compromised could be used to identify such compounds that normally fail to show up in screens; these compounds could then be more rationally designed to increase their bioavailability. This strategy was tested with transgenic Drosophila lines with altered expression of Cyp6g1 and Dhr96.
  
  
  RESULTS
  It was observed that Cyp6g1 knockdown transgenic lines have increased susceptibility to the test compound imidacloprid, while Dhr96 knockdown transgenic lines are resistant. Evidence was found for a systemic response to xenobiotic exposure, uncovered by piperonyl butoxide treatment and by gene expression profiling. Sex-specific gene expression regulated by DHR96 was also observed.
  
  
  CONCLUSIONS
  The results confirm that this approach to chemical discovery could identify compounds that escape traditional screens. The complexity of the system means that a panel of single and multiple gene knockdown transgenic lines may be required.
authors.affiliation: Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire, UK. Sheetal.shah@syngenta.com
authors.forename: Sheetal
authors.initials: S
authors.lastname: Shah
authors.forename: Carol
authors.initials: C
authors.lastname: Yarrow
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dunning
authors.forename: Ben
authors.initials: B
authors.lastname: Cheek
authors.forename: Simon
authors.initials: S
authors.lastname: Vass
authors.forename: John
authors.initials: J
authors.lastname: Windass
authors.forename: Stephen
authors.initials: S
authors.lastname: Hadfield
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D001681:Biological Assay; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007306:Insecticides / Q000378:metabolism* / Q000494:pharmacology; D000073943:Neonicotinoids; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C096796:Hr96 protein, Drosophila; D007093:Imidazoles; D007306:Insecticides; D000073943:Neonicotinoids; D009574:Nitro Compounds; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; C082359:imidacloprid; D003577:Cytochrome P-450 Enzyme System; C446928:Cyp6g1 protein, Drosophila; C082360:fipronil