title: Enzymes and inhibitors in neonicotinoid insecticide metabolism.
abstract: Neonicotinoid insecticide metabolism involves considerable substrate specificity and regioselectivity of the relevant CYP450, aldehyde oxidase, and phase II enzymes. Human CYP450 recombinant enzymes carry out the following conversions: CYP3A4, 2C19, and 2B6 for thiamethoxam (TMX) to clothianidin (CLO); 3A4, 2C19, and 2A6 for CLO to desmethyl-CLO; 2C19 for TMX to desmethyl-TMX. Human liver aldehyde oxidase reduces the nitro substituent of CLO to nitroso much more rapidly than it does that of TMX. Imidacloprid (IMI), CLO, and several of their metabolites do not give detectable N-glucuronides but 5-hydroxy-IMI, 4,5-diol-IMI, and 4-hydroxythiacloprid are converted to O-glucuronides in vitro with mouse liver microsomes and UDP-glucuronic acid or in vivo in mice. Mouse liver cytosol with S-adenosylmethionine converts desmethyl-CLO to CLO but not desmethyl-TMX to TMX. Two organophosphorus CYP450 inhibitors partially block IMI, thiacloprid, and CLO metabolism in vivo in mice, elevating brain and liver levels of the parent compounds while reducing amounts of the hydroxylated metabolites.
authors.affiliation: Department of Environmental Science, Environmental Chemistry and Toxicology Laboratory, University of California, Berkeley, California 94720-3112, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Shi
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Dick
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Ford
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D000073943:Neonicotinoids; D009574:Nitro Compounds / Q000737:chemistry / Q000378:metabolism*; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D000077922:Thiamethoxam; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D007093:Imidazoles; D007306:Insecticides; D000073943:Neonicotinoids; D009574:Nitro Compounds; D010078:Oxazines; D013844:Thiazoles; C480342:clothianidin; C082359:imidacloprid; D000077922:Thiamethoxam; D003577:Cytochrome P-450 Enzyme System; D042931:Aldehyde Oxidase