de Medeiros Hyllana Catarine Dias, Constantin Jorgete, Ishii-Iwamoto Emy Luiza, Mingatto Fábio Erminio
Laboratório de Bioquímica Metabólica e Toxicológica, UNESP - Univ Estadual Paulista, Campus de Dracena, 17900-000 Dracena, SP, Brazil.
Laboratório de Oxidações Biológicas, Departamento de Bioquímica, Universidade Estadual de Maringá, 87020-900 Maringá, PR, Brazil.
Toxicol Lett. 2015 Jul 2;236(1):34-42. doi: 10.1016/j.toxlet.2015.04.016. Epub 2015 May 2.
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.
氟虫腈是一种用于控制动植物害虫的杀虫剂，可导致动物和人类肝毒性，它在肝脏中通过细胞色素P-450代谢为氟虫腈砜。本研究旨在表征氟虫腈（10 - 50μM）对离体灌注大鼠肝脏能量代谢的影响。在喂食的动物中，糖原分解产生的葡萄糖和乳酸释放增加，表明糖原分解和糖酵解受到刺激。在禁食动物的肝脏中，氟虫腈抑制外源性L-丙氨酸生成葡萄糖和尿素，而氨和乳酸生成增加。此外，50μM浓度的氟虫腈在糖酵解条件下抑制氧气摄取并增加胞质NADH/NAD⁺比值。在正常或经丙胺苯丙酮预处理的大鼠肝脏中均发现了代谢改变，表明氟虫腈及其活性代谢产物促成了观察到的活性。对氧气摄取的影响表明，氟虫腈可能的毒性机制涉及线粒体呼吸活性受损，因此干扰能量代谢。用丙胺苯丙酮预处理大鼠可消除在最高浓度50μM时观察到的对氧气摄取的抑制作用，表明氟虫腈的代谢产物，包括氟虫腈砜，主要作为呼吸链抑制剂起作用。正常或经丙胺苯丙酮预处理的大鼠肝脏流出灌注液中乳酸脱氢酶活性的增加证实了母体化合物及其活性代谢产物的肝毒性。
