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 c is - 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.