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Risk assessment of the chiral pesticide prothioconazole in human models: in vitro-in vivo correlation, prediction of drug-pesticide interaction and cyto- and genotoxicity studies

Grant number: 20/02139-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2020
Effective date (End): August 31, 2023
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Analytical Chemistry
Principal Investigator:Anderson Rodrigo Moraes de Oliveira
Grantee:Icaro Salgado Perovani
Home Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Worldwide, the pesticides use has been significantly increasing. Hence, non-target organisms, such as humans, may be more exposed to its toxic effects. Prothioconazole is a fungicide used in Brazil, the United States of America and European Union countries in cotton, barley, corn and wheat crops. Since it is a chiral fungicide, each enantiomer may interact differently in chiral environments, such as organisms' biomolecules, which leads to enantioselective behavior. Some studies have demonstrated the prothioconazole enantioselective behavior in different environments, this represents indication that its metabolism in the human organism may be enantioselective. In this sense, the goal of this research project will be to perform a wide study with different human models aiming further risk assessment of the pesticide. For this purpose, the enantioselective metabolism of prothioconazole will be performed using human liver microsomes and further in vitro-in vivo correlation to determine the toxicokinetic parameters (i) hepatic clearance; (ii) hepatic extraction ratio and (iii) bioavailable fraction of the fungicide. Reaction phenotyping and inhibition studies of the main cytochrome P450 (CYP450) isoforms responsible for drug metabolism will be performed for assessment of drug-pesticide interactions. At last, cyto- and genotoxicity enantioselective studies will be performed to evaluate if the pesticide may present enantioselective toxicity to human cells. The studies will be conducted with the racemic mixture and the isolated enantiomers to compare the results. (AU)