Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes
Chieri Fujino,
Yoko Watanabe,
Seigo Sanoh,
Hiroyuki Nakajima,
Naoto Uramaru,
Hiroyuki Kojima,
Kouichi Yoshinari,
Shigeru Ohta,
Shigeyuki Kitamura
Affiliations
Chieri Fujino
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan; Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan; Corresponding author.
Yoko Watanabe
Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan
Seigo Sanoh
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
Hiroyuki Nakajima
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aoba, Aoba-ku, Sendai, 980-8578, Japan; School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
Naoto Uramaru
Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan
Hiroyuki Kojima
School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan; Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo, 060-0819, Japan
Kouichi Yoshinari
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
Shigeru Ohta
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan; Wakayama Medical University; 811-1 Kimiidera, Wakayama City, Wakayama, 641-8509, Japan
Shigeyuki Kitamura
Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan
In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to understand the effects of metabolic modification on their activities. All eight pyrethroids tested in this study showed rat PXR agonistic activity; deltamethrin was the most potent, followed by cis-permethrin and cypermethrin. However, when the pyrethroids were incubated with rat liver microsomes, their rat PXR activities were decreased to various extents. Cis- and trans-permethrin showed weak rat CAR agonistic activity, while the other pyrethroids were inactive. However, fenvalerate showed dose-dependent inverse agonistic activity toward rat CAR, and this activity was reduced after metabolism. None of the pyrethroids showed rat PPARα agonistic activity, but a metabolite of cis-/trans-permethrin and phenothrin, 3-phenoxybenzoic acid, activated rat PPARα. Since PXR, CAR and PPARα regulate various xenobiotic/endobiotic-metabolizing enzymes, activation of these receptors by pyrethroids may result in endocrine disruption due to changes of hormone-metabolizing activities.
