Oxidative stress and cell death induction by amitraz and its metabolite BTS-27271 mediated through cytochrome P450 and NRF2 pathway alteration in primary hippocampal cell

• Published in: Food and chemical toxicology 2019-07, Vol.129, p.87-96
• Main Authors: Moyano, Paula, Ruiz, Matilde, García, José Manuel, Frejo, María Teresa, Anadon Baselga, María José, Lobo, Margarita, García, Jimena, Del Pino, Javier
• Format: Article
• Language: English
• Subjects: Amitraz; BTS-27271 primary hippocampal cells; Cytochrome P450; NRF2; ROS
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2019.04.042

Amitraz is a neurotoxic formamidine pesticide that induces cell death in hippocampal neurons, although its mechanisms are unknown. Amitraz produces reactive oxygen species (ROS), which could lead to cell death. Amitraz was shown to induce different cytochrome P450 (CYP) isoenzymes involved with ROS and apoptotic cell death induction. Finally, amitraz was described to decrease the activity of antioxidant enzymes regulated through KEAP1/NRF2 pathway, thus likely leading to a reduction of ROS elimination and to cell death induction. We evaluated the effect of amitraz or BTS-27271 co-treatment with or without the antioxidant N-acetylcysteine and/or the unspecific CYP inhibitor 1-aminobenzotriazole on cell viability and its related mechanisms in wild type and silenced primary hippocampal neurons after 24 h treatment. We observed that amitraz produced oxidative stress and CYPs induction leading to apoptotic cell death. ROS generation was partially mediated by CYPs induction and downregulation of NRF2-pathway through KEAP1 overexpression. These data could help explain the mechanism by which amitraz induces cell death and oxidative stress and provide a therapeutic strategy to protect against this effect in case of poisoning. •AMZ and BTS-27271 induces oxidative stress and apoptotic cell death on primary hippocampal neurons.•AMZ and BTS-27271 produce oxidative stress through CYPs 1A1/2, 2B1/2, 2E1 and 3A1 induction and NRF2-pathway impairment.•AMZ and BTS-27271 induce cell death partially through oxidative stress generation and CYP induction.