Tange Satoko, Fujimoto Nariaki, Uramaru Naoto, Sugihara Kazumi, Ohta Shigeru, Kitamura Shigeyuki
Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
Environ Toxicol Pharmacol. 2014 May;37(3):996-1005. doi: 10.1016/j.etap.2014.03.009. Epub 2014 Mar 21.
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.
氯菊酯是一种广泛应用的广谱拟除虫菊酯类杀虫剂，由顺式和反式异构体的混合物组成。我们研究了异构体代谢后雌激素和抗雄激素活性的变化。顺式和反式氯菊酯均可被大鼠肝微粒体水解为3-苯氧基苄醇（PBAlc），但反式氯菊酯的水解程度远大于顺式异构体。在NADPH存在下，PBAlc进一步转化为4'-羟基化PBAlc（4'-OH PBAlc）、3-苯氧基苯甲醛（PBAld）和3-苯氧基苯甲酸（PBAcid）。顺式氯菊酯而非反式氯菊酯也产生了其4'-羟基化衍生物（4'-OH顺式氯菊酯）。反式氯菊酯是一种抗雄激素，但也表现出弱雌激素活性，而顺式氯菊酯是一种弱雌激素和弱抗雄激素。在NADPH存在下与大鼠肝微粒体孵育后，顺式氯菊酯而非反式氯菊酯的雌激素活性被代谢激活。另一方面，反式氯菊酯的雌激素活性未改变，但其抗雄激素活性在孵育后增强。4'-OH PBAlc和PBAlc表现出雌激素活性，而PBAld和PBAlc表现出抗雄激素活性。PBAcid没有表现出任何活性。4'-OH顺式氯菊酯表现出雌激素和抗雄激素活性。总体而言，我们的结果表明氯菊酯在雌激素和抗雄激素活性方面被代谢激活，氯菊酯向4'-OH顺式氯菊酯、4'-OH PBAlc和PBAlc的微粒体转化有助于这两种代谢激活。
