In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes

Autor(es)

Perovani, Icaro Salgado ; Santos Barbetta, Maike Felipe ; da Silva, Rodrigo Moreira ; Lopes, Norberto Peporine ; Moraes de Oliveira, Anderson Rodrigo

• Tipo de documento: Artigo Científico
• Fonte: Food and Chemical Toxicology; v. 163, p. 8-pg., 2022-03-22.

Resumo

Growing human demand for food has culminated in increased use of pesticides worldwide. Prothioconazole (PTC), a profungicide, is bioactivated by metabolic PTC oxidation to prothioconazole-desthio (D-PTC). Here, the in vitro phase I metabolism of PTC to D-PTC in human liver microsomes and human CYP450 forms was studied. The kinetic parameters for the formation of (+)-D-PTC (K-M = 1.2 mu mol L-1, V-MAX = 1.7 pmol min(- 1) mg( -1)), (-)-D-PTC (K-M = 7 mu mol L-1, V-MAX = 5.1 pmol min(- 1 )mg (-1)), and both D-PTC enantiomers (KM = 9 mu mol L-1, V-MAX = 7 pmol min- 1 mg( -1)) from rac-PTC indicated an enantioselective behavior. Formation of the enantiomer (+)-D-PTC was twice more extensive than the formation of the enantiomer (-)-D-PTC. Furthermore, CLH prediction revealed the same enantioselective behavior. The phenotyping study indicated that CYP2C19 was the sole CYP450 form accounting for the metabolism of PTC. The estimated apparent distribution volume of PTC was predicted as 2 L kg( -1). This study showed that D-PTC may be formed in the human organism due to hepatic metabolism of PTC, mediated by CYP2C19 and that the enantiomer (+)-D-PTC is preferentially formed. However, it was not extensively formed (~1%). Considering a risk assessment point of view, this study provided positive evidence of PTC safety. (AU)

• Processo FAPESP: 21/10098-4 - Avaliação enantiosseletiva in vitro do efeito de praguicidas quirais sobre as principais enzimas do citocromo P450 de humanos envolvidas no metabolismo de fármacos: correlação in vitro-in vivo e predição de interação praguicida-fármaco
• Beneficiário: Anderson Rodrigo Moraes de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/02139-0 - Avaliação de risco do praguicida quiral protioconazol em modelos humanos: correlação in vitro-in vivo, predição de interação medicamentosa e estudos de cito- e genotoxicidade
• Beneficiário: Icaro Salgado Perovani
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/50945-4 - INCT 2014: Instituto Nacional de Tecnologias Alternativas para Detecção, Avaliação Toxicológica e Remoção de Micropoluentes e Radioativos
• Beneficiário: Maria Valnice Boldrin
• Modalidade de apoio: Auxílio à Pesquisa - Temático