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

doi:10.1016/j.heliyon.2019.e02466

Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes

Heliyon. 2019 Sep 12;5(9):e02466. doi: 10.1016/j.heliyon.2019.e02466. eCollection 2019 Sep.

Authors

Chieri Fujino^{1

2}, Yoko Watanabe², Seigo Sanoh¹, Hiroyuki Nakajima^{3

4}, Naoto Uramaru², Hiroyuki Kojima^{5

6}, Kouichi Yoshinari⁴, Shigeru Ohta^{1

7}, Shigeyuki Kitamura²

Affiliations

¹ Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
² Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan.
³ Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aoba, Aoba-ku, Sendai, 980-8578, Japan.
⁴ School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
⁵ School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
⁶ Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo, 060-0819, Japan.
⁷ Wakayama Medical University; 811-1 Kimiidera, Wakayama City, Wakayama, 641-8509, Japan.

Abstract

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.

Keywords: CAR; Environmental health; Environmental science; Liver microsomes; Nuclear receptor activation; PPARα; PXR; Pesticide; Pyrethroid pesticide; Toxicology.