title: An evaluation of the cytochrome P450 inhibition potential of selected pesticides in human hepatic microsomes.
abstract: The goal of this work was to study the ability of 18 pesticides to inhibit selective model activities for all major xenobiotic-metabolizing enzymes, namely CYP1A1/2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Generally organophosphorus insecticides were the most potent and extensive inhibitors, especially towards CYP1A1/2 (IC(50) values of chlorpyrifos, fenitrothion and profenofos approximately 3 micro M), CYP2B6 (IC(50) values of chlorpyrifos and fenitrothion 2.5 micro M), CYP2C8 (fenitrothion 4.3 micro M), CYP2C9 (fenitrothion and malathion 4.8 and 2.5 micro M, respectively), CYP2D6 (chlorpyrifos and phenthoate approximately 3 micro M) and CYP3A4 (chlorpyrifos, fenitrothion and phenthoate 3-4 micro M). Otherwise there were quite considerable differences in potency and extent of inhibition between different organophosphates. Pyrethroids were in general very weak or inactive. Deltamethrin and fenvalerate were potent inhibitors of CYP2D6 (IC(50) values of approximately 3 micro M) while lambda-cyhalothrin potently inhibited both CYP2D6 and CYP3A4-mediated activities (IC(50)'s about 3-4 micro M). Some pesticides caused relatively potent inhibitions sporadically (carbendazim, CYP2D6, IC(50) = 12 micro M; atrazine, CYP3A4, IC(50) = 2.8 micro M; glyphosate, CYP2C9, IC(50) = 3.7 micro M; hexaflumuron, IC(50) = 6.0 micro M). With the exceptions of alpha-cypermethrin, cypermethrin, isoproturon, carbaryl and abamectin, most pesticides inhibited relatively potently at least one CYP-selective activity, which may have relevance for potential interactions in occupational exposures and for further studies on the CYP-associated metabolism of respective pesticides.
authors.affiliation: Pharmacology and Toxicology Unit, Institute of Biomedicine, University of Oulu, Oulu, Finland. khaled.megahed@oulu.fi
authors.forename: Khaled
authors.initials: K
authors.lastname: Abass
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D010575:Pesticides / Q000494:pharmacology*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D010575:Pesticides; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8