title: Evaluation of the stereoselective biotransformation of permethrin in human liver microsomes: contributions of cytochrome P450 monooxygenases to the formation of estrogenic metabolites.
abstract: Permethrin (PM) is a pyrethroid insecticide that exists as 4 enantiomers. Biotransformation of PM to estrogen receptor agonists (3-phenoxybenzyl alcohol (PBOH) and 3-(4'-hydroxyphenoxy)-benzyl alcohol (3,4 PBOH)) has been shown to be stereoselective in other vertebrate species. This study evaluated the biotransformation of PM enantiomers in human liver microsomes and with recombinant CYP3A4 and CYP2C19. PBOH and 3,4 PBOH were the only metabolites detected from in vitro incubations including each of the 4 enantiomers of PM with 1R-trans PM having the most efficient NADPH-catalyzed biotransformation to both metabolites. Coincubation with the CYP inhibitor ketoconazole and time course experiments with liver microsomes and recombinant CYP2C19 and CYP3A4 indicated CYP-catalyzed stereoselective cleavage of the ester followed by 4-hydoxylation to 3,4' PBOH. These data indicate potential dispositional differences may occur with PM enantiomers and a shift in putative molecular targets. While cleavage of pyrethroid esters lead to detoxification of the acute neurological effects, formation of the benzyl alcohol and hydroxylated metabolite may lead to estrogenic responses, since each of these metabolites are estrogen receptor ligands.
authors.affiliation: Department of Environmental Sciences, University of California, Riverside, CA 92521, United States.
authors.forename: Ramon
authors.initials: R
authors.lastname: Lavado
authors.affiliation: Department of Environmental Sciences, University of California, Riverside, CA 92521, United States.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Environmental Sciences, University of California, Riverside, CA 92521, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Rimoldi
authors.affiliation: Department of Environmental Sciences, University of California, Riverside, CA 92521, United States. Electronic address: daniel.schlenk@ucr.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlenk
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001592:Benzyl Alcohols / Q000378:metabolism; D001711:Biotransformation; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D006900:Hydroxylation; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D026023:Permethrin / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D001592:Benzyl Alcohols; D004791:Enzyme Inhibitors; D004967:Estrogens; D007306:Insecticides; D011994:Recombinant Proteins; C064809:3-phenoxybenzylalcohol; D026023:Permethrin; D009249:NADP; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Biotransformation; Cytochrome P450; Estrogenic activity; Microsomes; Permethrin; Pyrethroids