title: Stereoselective biotransformation of permethrin to estrogenic metabolites in fish.
abstract: This study investigated the stereoselective biotransformation and resulting estrogenic activity of the pyrethroid insecticide, permethrin (PM). Results of both in vivo (male Japanese medaka, vitellogenin (VTG) protein in plasma) and in vitro (primary rainbow trout hepatocyte VTG-mRNA expression) assays indicated stereoselective estrogenic activity of PM. 1S-cis-PM was observed to have significantly higher activity (P ≤ 0.05) than the 1R-cis enantiomer in both in vivo and in vitro evaluations. All enantiomers of PM were oxidized to a 4'-hydoxy PM (4OH PM) metabolite and underwent esterase cleavage to 3-phenoxybenzyl alcohol (3-PBOH) and 3-(4'-hydroxyphenoxy)-benzyl alcohol) (3,4'-PBOH). Racemic 4OH PM as well as 3-PBOH, and 3,4'-PBOH possessed significant (P ≤ 0.05) estrogenicity. 1S-trans-PM underwent esterase cleavage more extensively than the corresponding 1R-trans-PM. Inhibition studies with ketoconazole confirmed cytochrome P450-catalyzed hydroxylation as well as esterase cleavage of PM for all stereoisomers. These studies indicated stereoselectivity in the estrogenic activity of PM resulting from stereoselective biotransformation of the parent compound to more estrogenic metabolites.
authors.affiliation: Department of Environmental Sciences, University of California, Riverside, California 92521, USA.
authors.forename: Mae Grace
authors.initials: MG
authors.lastname: Nillos
authors.forename: Sarah
authors.initials: S
authors.lastname: Chajkowski
authors.forename: John M
authors.initials: JM
authors.lastname: Rimoldi
authors.forename: Jay
authors.initials: J
authors.lastname: Gan
authors.forename: Ramon
authors.initials: R
authors.lastname: Lavado
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlenk
mesh_terms: D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005399:Fishes / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006900:Hydroxylation; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D017686:Oncorhynchus mykiss / Q000378:metabolism; D009990:Oryzias / Q000378:metabolism; D026023:Permethrin / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D014819:Vitellogenins / Q000378:metabolism
chemical_list: D004967:Estrogens; D007306:Insecticides; D014819:Vitellogenins; D026023:Permethrin; D003577:Cytochrome P-450 Enzyme System; D004950:Esterases