title: Imidacloprid insecticide metabolism: human cytochrome P450 isozymes differ in selectivity for imidazolidine oxidation versus nitroimine reduction.
abstract: Many metabolites of imidacloprid (IMI) have been identified, but the enzymatic basis for their formation has not been reported. This study with individual recombinant cytochrome P450 (CYP450) isozymes from human liver shows that the principal organoextractable NADPH-dependent metabolites are the 5-hydroxy (major) and olefin (minor) derivatives from hydroxylation and desaturation of the imidazolidine moiety and the nitrosoimine (major), guanidine (minor) and urea (trace) derivatives from reduction and cleavage of the nitroimine substituent. Isozymes selective for imidazolidine oxidation in order of decreasing overall activity are CYP3A4>CYP2C19 or CYP2A6>CYP2C9, while those selective for nitroimine reduction are CYP1A2, CYP2B6, CYP2D6 and CYP2E1. Three flavin monooxygenase isozymes (FMO1, FMO3, and FMO5) with NADPH are not active as assayed. These observations establish site specificity in IMI metabolism by CYP450 isozymes and that a single enzyme (CYP3A4) both oxidizes and reduces IMI at the imidazolidine and nitroimine moieties, respectively.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Schulz-Jander
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D001711:Biotransformation; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000633:toxicity; D007097:Imines / Q000378:metabolism*; D007306:Insecticides / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D000073943:Neonicotinoids; D009574:Nitro Compounds; D010084:Oxidation-Reduction; D010944:Plants; D011994:Recombinant Proteins / Q000378:metabolism; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013379:Substrate Specificity
chemical_list: D007093:Imidazoles; D007097:Imines; D007306:Insecticides; D007527:Isoenzymes; D000073943:Neonicotinoids; D009574:Nitro Compounds; D011994:Recombinant Proteins; D012997:Solvents; C082359:imidacloprid; D003577:Cytochrome P-450 Enzyme System