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

• Published in: Heliyon 2019-09, Vol.5 (9), p.e02466-e02466, Article e02466
• Main Authors: Fujino, Chieri, Watanabe, Yoko, Sanoh, Seigo, Nakajima, Hiroyuki, Uramaru, Naoto, Kojima, Hiroyuki, Yoshinari, Kouichi, Ohta, Shigeru, Kitamura, Shigeyuki
• Format: Article
• Language: English
• Subjects: CAR; Environmental health; Environmental science; Liver microsomes; Nuclear receptor activation; Pesticide; PPARα; PXR; Pyrethroid pesticide; Toxicology
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2019.e02466

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.