title: Fipronil induces CYP isoforms in rats.
abstract: The goal of the present study was to evaluate fipronil effects on the activities of drug metabolizing enzymes in rat liver microsomes. Rats were orally treated with fipronil at doses of 1, 5, 10 and 15 mg/kg bw/day for 6 days. Determinations of cytochrome P450 (CYP) enzyme activities were carried out in hepatic microsomes isolated from treated rats. The activities of some members of CYP2E, CYP1A, CYP2A, CYP2B and CYP3A subfamilies significantly increased after fipronil treatment in a dose-dependent manner as compared to control. The major effects were observed in the O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin (reflecting CYP1A1/2 activities), in the O-depenthylation of pentoxyresorufin and 16β-hydroxylation of testosterone (reflecting CYP2B1/2 activities), and in the N-demethylation of erythromycin and 6β-hydroxylation of testosterone (reflecting CYP3A1/2 activities). Immunoblot studies revealed that fipronil increased the apoprotein levels of CYP1A1. Our results suggest that fipronil is an inducer of hepatic phase I CYP enzymes, causing an increased potential to interact with a wide range of xenobiotics or endogenous chemicals that are substrates of the CYP1A, CYP2B and CYP3A subfamilies. Further investigations are required to in vivo evaluate the potential of the metabolite fipronil sulfone as an inducer of phase I CYP enzymes.
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: M V
authors.initials: MV
authors.lastname: Caballero
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ares
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martínez
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: M R
authors.initials: MR
authors.lastname: Martínez-Larrañaga
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain. Electronic address: anadon@vet.ucm.es.
authors.forename: A
authors.initials: A
authors.lastname: Anadón
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Martínez
mesh_terms: D000818:Animals; D065693:Cytochrome P-450 Enzyme Inducers / Q000008:administration & dosage / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011720:Pyrazoles / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D017208:Rats, Wistar
chemical_list: D065693:Cytochrome P-450 Enzyme Inducers; D007306:Insecticides; D007527:Isoenzymes; D011720:Pyrazoles; D003577:Cytochrome P-450 Enzyme System; C082360:fipronil
keywords: Cytochrome P450 enzymes; Fipronil; Hepatic microsomes; Rats