title: In vitro metabolism of cis- and trans-permethrin by rat liver microsomes, and its effect on estrogenic and anti-androgenic activities.
abstract: Permethrin is a widely applied broad-spectrum pyrethroid insecticide that consists of a mixture of cis- and trans-isomers. We examined the changes of estrogenic and anti-androgenic activities resulting from metabolism of the isomers. Both cis- and trans-permethrin were hydrolyzed to 3-phenoxybenzyl alcohol (PBAlc) by rat liver microsomes, but the extent of hydrolysis of trans-permethrin was much greater than that of the cis-isomer. In the presence of NADPH, PBAlc was further transformed to 4'-hydroxylated PBAlc (4'-OH PBAlc), 3-phenoxybenzaldehyde (PBAld) and 3-phenoxybenzoic acid (PBAcid). cis-Permethrin, but not trans-permethrin, also afforded its 4'-hydroxylated derivative (4'-OH cis-permethrin). trans-Permethrin was an anti-androgen, but also showed weak estrogenic activity, while cis-permethrin was a weak estrogen and a weak anti-androgen. After incubation with rat liver microsomes in the presence of NADPH, cis-permethrin but not trans-permethrin was metabolically activated for estrogenic activity. On the other hand, estrogenic activity of trans-permethrin was not changed, but its anti-androgenic activity was enhanced after incubation. 4'-OH PBAlc and PBAlc showed estrogenic activity, while PBAld and PBAlc showed anti-androgenic activity. PBAcid showed neither activity. 4'-OH cis-permethrin showed both estrogenic and anti-androgenic activities. Overall, our results indicate that permethrin is metabolically activated for estrogenic and anti-androgen activities, and the microsomal transformation of permethrin to 4'-OH cis-permethrin, 4'-OH PBAlc and PBAlc contributes to the both metabolic activations.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Tange
authors.affiliation: Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Nariaki
authors.initials: N
authors.lastname: Fujimoto
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Uramaru
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Hirokoshingai 5-1-1, Kure, Hiroshima 737-0112, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan. Electronic address: kitamura@nichiyaku.ac.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D001547:Benzaldehydes / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D001592:Benzyl Alcohols / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D006868:Hydrolysis; D007306:Insecticides / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D026023:Permethrin / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D020218:Response Elements
chemical_list: D001547:Benzaldehydes; D001565:Benzoates; D001592:Benzyl Alcohols; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D007306:Insecticides; C064809:3-phenoxybenzylalcohol; C064808:3-phenoxybenzaldehyde; D026023:Permethrin; C017618:3-phenoxybenzoic acid; D010088:Oxidoreductases; D008156:Luciferases; D006867:Hydrolases
keywords: 3-Phenoxybenzyl alcohol; Anti-androgenic activity; Estrogenic activity; Rat liver microsomes; cis-Permethrin; trans-Permethrin