In vitro enantioselective inhibition of the main human CYP450 enzymes involved in drug metabolism by the chiral pesticide tebuconazole

Registro completo de metadados
MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniversidade de São Paulo (USP)-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.creatorHabenschus, Maísa Daniela-
Autor(es): dc.creatorCarrão, Daniel Blascke-
Autor(es): dc.creatorde Albuquerque, Nayara Cristina Perez-
Autor(es): dc.creatorPerovani, Icaro Salgado-
Autor(es): dc.creatorMoreira da Silva, Rodrigo-
Autor(es): dc.creatorNardini, Viviani-
Autor(es): dc.creatorLopes, Norberto Peporine-
Autor(es): dc.creatorDias, Luís Gustavo-
Autor(es): dc.creatorMoraes de Oliveira, Anderson Rodrigo [UNESP]-
Data de aceite: dc.date.accessioned2022-08-04T22:11:56Z-
Data de disponibilização: dc.date.available2022-08-04T22:11:56Z-
Data de envio: dc.date.issued2022-04-28-
Data de envio: dc.date.issued2022-04-28-
Data de envio: dc.date.issued2021-10-15-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.toxlet.2021.08.006-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/222262-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/222262-
Descrição: dc.descriptionTebuconazole (TEB) is a chiral triazole fungicide worldwide employed to control plant pathogens and preserve wood. People can be exposed to TEB either through diet and occupational contamination. This work investigates the in vitro inhibitory potential of rac-TEB, S-(+)-TEB, and R-(−)-TEB over the main cytochrome P450 enzymes (CYP450) using human liver microsomes to predict TEB in vivo inhibition potential. The IC50 values showed that in vitro inhibition was enantioselective for CYP2C9, CYP2C19, and CYP2D6, but not for CYP3A4/5. Despite enantioselectivity, rac-TEB and its single enantiomers were always classified in the same category. The inhibition mechanisms and constants were determined for rac-TEB and it has shown to be a mixed inhibitor of CYP3A4/5 (Ki = 1.3 ± 0.3 μM, αKi = 3.2 ± 0.5 μM; Ki = 0.6 ± 0.3 μM, αKi = 1.3 ± 0.3 μM) and CYP2C9 (Ki = 0.7 ± 0.1 μM, αKi = 2.7 ± 0.5 μM), and a competitive inhibitor of CYP2D6 (Ki = 11.9 ± 0.7 μM) and CYP2C19 (Ki = 0.23 ± 0.02 μM), respectively, suggesting that in some cases, rac-TEB has a higher or comparable inhibitory potential than well-known strong inhibitors of CYP450 enzymes, especially for CYP2C9 and CYP2C19. In vitro-in vivo extrapolations (IVIVE) were conducted based on the results and data available in the literature about TEB absorption and metabolism. R1 values were estimated based on the Food and Drug Administration guideline and suggested that in a chronic oral exposure scenario considering the acceptable daily intake dose proposed by the European Food and Safety Authority, the hypothesis of rac-TEB to inhibit the activities of CYP3A4/5, CYP2C9, and CYP2C19 in vivo and cause pesticide-drug interactions cannot be disregarded.-
Descrição: dc.descriptionDepartamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo-
Descrição: dc.descriptionDepartamento de Física e Química Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo-
Descrição: dc.descriptionNational Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355-
Descrição: dc.descriptionNational Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355-
Formato: dc.format1-9-
Idioma: dc.languageen-
Relação: dc.relationToxicology Letters-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectChiral-
Palavras-chave: dc.subjectCytochrome P450-
Palavras-chave: dc.subjectEnantioselective-
Palavras-chave: dc.subjectHuman liver microsomes-
Palavras-chave: dc.subjectInhibition-
Palavras-chave: dc.subjectTebuconazole-
Título: dc.titleIn vitro enantioselective inhibition of the main human CYP450 enzymes involved in drug metabolism by the chiral pesticide tebuconazole-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

Não existem arquivos associados a este item.