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Mitochondrial disfunction in the toxicity of the insecticide Diazinon in HepG2 cells and therapeutic potential of tetrahydrocurcurmin

Grant number: 18/22002-9
Support type:Regular Research Grants
Duration: May 01, 2019 - April 30, 2021
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Fábio Erminio Mingatto
Grantee:Fábio Erminio Mingatto
Home Institution: Faculdade de Ciências Agrárias e Tecnológicas. Universidade Estadual Paulista (UNESP). Campus de Dracena. Dracena , SP, Brazil
Assoc. researchers:Daniel Junqueira Dorta

Abstract

Diazinon is an organophosphate insecticide widely used in agriculture for pest control, in veterinary medicine as antiparasitic, mainly in production animals, as well as in the control of domestic pests. There are several reports in the literature of animal and human poisoning caused by the substance and the liver is one of the affected organs. Previous studies have indicated that changes in redox balance and mitochondrial dysfunction are involved in the toxicity produced by diazinon, however there is a shortage of studies on the mechanisms of action of diazinon on mitochondria and their real role in cell death, as well as on the effect of the biotransformation of the insecticide on its toxicity. Mitochondria are responsible for the synthesis of almost all of the ATP necessary to maintain cell structure and function. They are also the main intracellular sources and important targets of reactive oxygen species, which, in association with calcium, can induce the mitochondrial membrane permeability transition (MPT), which can lead to cell death. Thus, this organelle has become an attractive study target for the development of new therapies for the treatment of xenobiotic diseases and intoxications. In pilot experiments performed in our laboratory with mitochondria isolated from rat liver, it was observed that diazinon interferes in the oxygen consumption of the mitochondria, dissipates mitochondrial membrane potential and inhibits mitochondrial ATP synthesis in the concentration range of 50 to 150 µM . Further analyzes to evaluate the effect of insecticide on mitochondrial parameters related to the production of reactive oxygen species (ROS), oxidative status and induction of MPT showed that diazinon does not induce the production of ROS but promotes the oxidation of pyridine nucleotides and of thiol groups of proteins associated with the calcium efflux, induction of MPT and the release of cytochrome c. These preliminary results support the next proposed steps that will involve the study of modulating substances to understand the mechanisms by which the insecticide induces TPM in isolated mitochondria, as well as to evaluate the role of this organelle, the effect of biotransformation and the type of cell death on insecticide toxicity in HepG2 cells. Also, since the oxidation of thiol groups of proteins appears to be related to diazinon-promoted MPT, the protective effect of tetrahydrocurcumin, a phytochemical with a recognized antioxidant action, protecting thiols and antiapoptotic groups against the toxicity of diazinon in HepG2 cells. Thus, this study becomes interesting and of great value since the detailed understanding of the role of mitochondria and biotransformation in the toxicity induced by diazinon and the possible protective effect of tetrahydrocurcumin may contribute to the future use of therapies that act both in prevention and in the treatment of animals and humans intoxicated by the insecticide and other xenobiotics with similar mechanism of action. (AU)