Pyrethroid insecticide lambda-cyhalothrin induces hepatic cytochrome P450 enzymes, oxidative stress and apoptosis in rats María-Aránzazu Martínez ⁎, Irma Ares, José-Luis Rodríguez, Marta Martínez, David Roura-Martínez, Victor Castellano, Bernardo Lopez-Torres, María-Rosa Martínez-Larrañaga, Arturo Anadón Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain HIGHLIGHTS • Lambda-cyhalothrin induced hepatic CYP1A1/2, CYP2B1/2, CYP3A1/2, CYP4A1/2 activities in rats. • Similarly, an increase of hepatic CYP1A1/2, 2A1, 2B1/2, 2E1, 3A1/2 and 4A1 mRNA levels was observed. • IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions were also affected. • PCR array showed greater fold change on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes. • IPA groups genes into toxicological mechanisms related to fatty acid and xenobiotic metabolism. GRAPHICAL ABSTRACT abstract article info Article history: Received 13 December 2017 Received in revised form 23 January 2018 Accepted 3 March 2018 Available online xxxx Editor: Henner Hollert This study aimed to examine in rats the effects of the Type II pyrethroid lambda-cyhalothrin on hepatic micro- somal cytochrome P450 (CYP) isoform activities, oxidative stress markers, gene expression of proinflammatory, oxidative stress and apoptosis mediators, and CYP isoform gene expression and metabolism phase I enzyme PCR array analysis. Lambda-cyhalothrin, at oral doses of 1, 2, 4 and 8 mg/kg bw for 6 days, increased, in a dose-dependent manner, hepatic activities of ethoxyresorufin O-deethylase (CYP1A1), methoxyresorufin O-demethylase (CYP1A2), pentoxyresorufin O-depentylase (CYP2B1/2), testosterone 7α- (CYP2A1), 16β- (CYP2B1), and 6β-hydroxylase (CYP3A1/2), and lauric acid 11- and 12-hydroxylase (CYP4A1/2). Similarly, lambda-cyhalothrin (4 and 8 mg/kg bw, for 6 days), in a dose-dependent manner, increased significantly hepatic CYP1A1, 1A2, 2A1, 2B1, 2B2, 2E1, 3A1, 3A2 and 4A1 mRNA levels and IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions. PCR array analysis showed from 84 genes examined (P b 0.05; fold change N 1.5), changes in mRNA levels in 18 genes: 13 up-regulated and 5 down-regulated. A greater fold change reversion than 3-fold was observed on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes. Ingenuity Pathway Analysis (IPA) groups the expressed genes into biological mechanisms that are Keywords: Lambda-cyhalothrin Oral exposure Cytochrome P450 enzymes Gene expression Pathways Science of the Total Environment 631–632 (2018) 1371–1382 Abbreviations: ALDH1A1, aldehyde dehydrogenase 1 family, member A1; ALDH1B1, aldehyde dehydrogenase 1 family, member B1; ADH4, alcohol dehydrogenase 4 (class II), pi polypeptide; ADH6, alcohol dehydrogenase 6 (class V); ALDH3B1, aldehyde dehydrogenase 3 family, member B1; ARE, antioxidant response element; Bax, Bcl2-associated X protein; Bcl2, B-cell CLL/lymphoma 2; Casp-3, caspase-3; CYP, cytochrome P450; EROD, ethoxyresorufin O-deethylase; FMO5, flavin containing monooxygenase 5; GPx, glutathione peroxidase; GR, glutathione reductase; GSSG, glutathione oxidized; GST, glutathione S-transferase; HPRT1, hypoxanthine phosphoribosyltransferase 1; IL-1β, interleukin-1β; IPA, Ingenuity Pathway Analysis; LOAEL, lowest observed adverse effect level; MROD, methoxyresorufin O-demethylase; NFκB, nuclear factor kappa B; NOAEL, no observed adverse effect level; Nrf2, nuclear factor-erythroid-2 p45-related factor; p53, tumor protein p53; PROD, pentoxyresorufin O-depentylase; ROS, reactive oxygen species; RPLP1, ribosomal protein, large, P1; SOD, su- peroxide dismutase; XDH, xanthine dehydrogenase. ⁎ Corresponding author. E-mail address: arantxam@vet.ucm.es (M.-A. Martínez). https://doi.org/10.1016/j.scitotenv.2018.03.030 0048-9697/© 2018 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Science of the Total Environment journal homepage: www.elsevier.com/locate/scitotenv