title: Effect of fipronil on energy metabolism in the perfused rat liver.
abstract: Fipronil is an insecticide used to control pests in animals and plants that can causes hepatotoxicity in animals and humans, and it is hepatically metabolized to fipronil sulfone by cytochrome P-450. The present study aimed to characterize the effects of fipronil (10-50μM) on energy metabolism in isolated perfused rat livers. In fed animals, there was increased glucose and lactate release from glycogen catabolism, indicating the stimulation of glycogenolysis and glycolysis. In the livers of fasted animals, fipronil inhibited glucose and urea production from exogenous l-alanine, whereas ammonia and lactate production were increased. In addition, fipronil at 50μM concentration inhibited the oxygen uptake and increased the cytosolic NADH/NAD⁺ ratio under glycolytic conditions. The metabolic alterations were found both in livers from normal or proadifen-pretreated rats revealing that fipronil and its reactive metabolites contributed for the observed activity. The effects on oxygen uptake indicated that the possible mechanism of toxicity of fipronil involves impairment on mitochondrial respiratory activity, and therefore, interference with energy metabolism. The inhibitory effects on oxygen uptake observed at the highest concentration of 50μM was abolished by pretreatment of the rats with proadifen indicating that the metabolites of fipronil, including fipronil sulfone, acted predominantly as inhibitors of respiratory chain. The hepatoxicity of both the parent compound and its reactive metabolites was corroborated by the increase in the activity of lactate dehydrogenase in the effluent perfusate in livers from normal or proadifen-pretreated rats.
authors.affiliation: Laboratório de Bioquímica Metabólica e Toxicológica, UNESP - Univ Estadual Paulista, Campus de Dracena, 17900-000 Dracena, SP, Brazil.
authors.forename: Hyllana Catarine Dias
authors.initials: HC
authors.lastname: de Medeiros
authors.affiliation: Laboratório de Oxidações Biológicas, Departamento de Bioquímica, Universidade Estadual de Maringá, 87020-900 Maringá, PR, Brazil.
authors.forename: Jorgete
authors.initials: J
authors.lastname: Constantin
authors.affiliation: Laboratório de Oxidações Biológicas, Departamento de Bioquímica, Universidade Estadual de Maringá, 87020-900 Maringá, PR, Brazil.
authors.forename: Emy Luiza
authors.initials: EL
authors.lastname: Ishii-Iwamoto
authors.affiliation: Laboratório de Bioquímica Metabólica e Toxicológica, UNESP - Univ Estadual Paulista, Campus de Dracena, 17900-000 Dracena, SP, Brazil. Electronic address: fmingatto@dracena.unesp.br.
authors.forename: Fábio Erminio
authors.initials: FE
authors.lastname: Mingatto
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism*; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects; D050261:Glycogenolysis / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D049990:Membrane Transport Modulators / Q000378:metabolism / Q000633:toxicity*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D011335:Proadifen / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism / Q000633:toxicity*; D017208:Rats, Wistar; D014508:Urea / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D065607:Cytochrome P-450 Enzyme Inhibitors; D007306:Insecticides; D049990:Membrane Transport Modulators; D011720:Pyrazoles; D014508:Urea; D011335:Proadifen; C082360:fipronil
keywords: Energetic metabolism; Gluconeogenesis; Glycogenolysis; Glycolisis; Insecticides; Urea cycle