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  • In vitro metabolism of cis- and trans-permethrin by rat liver microsomes, and its effect on estrogenic and anti-androgenic activities.

In vitro metabolism of cis- and trans-permethrin by rat liver microsomes, and its effect on estrogenic and anti-androgenic activities.

Environmental toxicology and pharmacology (2014-04-16)
Satoko Tange, Nariaki Fujimoto, Naoto Uramaru, Kazumi Sugihara, Shigeru Ohta, Shigeyuki Kitamura
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.

MATERIALS
Product Number
Brand
Product Description

Flutamide, European Pharmacopoeia (EP) Reference Standard
Flutamide for system suitability, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Flutamide