Enantioselective inhibition of human CYP2C19 by the chiral pesticide ethofumesate: Prediction of pesticide-drug interactions in humans

Registro completo de metadados
MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniversidade de São Paulo (USP)-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.creatorPerovani, Icaro Salgado-
Autor(es): dc.creatorMariano Bucci, Jade Lorena-
Autor(es): dc.creatorCarrão, Daniel Blascke-
Autor(es): dc.creatorSantos Barbetta, Maike Felipe-
Autor(es): dc.creatorMoreira da Silva, Rodrigo-
Autor(es): dc.creatorLopes, Norberto Peporine-
Autor(es): dc.creatorMoraes de Oliveira, Anderson Rodrigo-
Data de aceite: dc.date.accessioned2025-08-21T19:29:35Z-
Data de disponibilização: dc.date.available2025-08-21T19:29:35Z-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2021-08-25-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.cbi.2021.109552-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/231463-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/231463-
Descrição: dc.descriptionEthofumesate is a chiral herbicide that may display enantioselective behavior in humans. For this reason, the enantioselective potential of ethofumesate and its main metabolite ethofumesate-2-hydroxy to cause pesticide-drug interactions on cytochrome P450 forms (CYPs) has been evaluated by using human liver microsomes. Among the evaluated CYPs, CYP2C19 had its activity decreased by the ethofumesate racemic mixture (rac-ETO), (+)-ethofumesate ((+)-ETO), and (−)-ethofumesate ((−)-ETO). CYP2C19 inhibition was not time-dependent, but a strong inhibition potential was observed for rac-ETO (IC50 = 5 ± 1 μmol L−1), (+)-ETO (IC50 = 1.6 ± 0.4 μmol L−1), and (−)-ETO (IC50 = 1.8 ± 0.4 μmol L−1). The reversible inhibition mechanism was competitive, and the inhibition constant (Ki) values for rac-ETO (2.6 ± 0.4 μmol L−1), (+)-ETO (1.5 ± 0.2 μmol L−1), and (−)-ETO (0.7 ± 0.1 μmol L−1) were comparable to the Ki values of strong CYP2C19 inhibitors. Inhibition of CYP2C19 by ethofumesate was enantioselective, being almost twice higher for (−)-ETO than for (+)-ETO, which indicates that this enantiomer may be a more potent inhibitor of this CYP form. For an in vitro-in vivo correlation, the Food and Drug Administration's (FDA) guideline on the assessment of drug-drug interactions used in the early stages of drug development was used. The FDA's R1 values were estimated on the basis of the obtained ethofumesate Ki and distribution volume, metabolism, unbound plasma fraction, gastrointestinal and dermal absorption data available in the literature. The correlation revealed that ethofumesate probably inhibits CYP2C19 in vivo for both chronic (oral) and occupational (dermal) exposure scenarios.-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-
Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionDepartamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo-
Descrição: dc.descriptionNúcleo de Pesquisas de Produtos Naturais e Sintéticos Departamento de Ciências Biomoleculares 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-
Descrição: dc.descriptionFAPESP: 2014/50945-4-
Descrição: dc.descriptionFAPESP: 2016/14668-7-
Descrição: dc.descriptionFAPESP: 2018/07534-4-
Descrição: dc.descriptionFAPESP: 2019/12149-5-
Descrição: dc.descriptionFAPESP: 2020/02139-0-
Descrição: dc.descriptionCNPq: 465571/2014-0-
Idioma: dc.languageen-
Relação: dc.relationChemico-Biological Interactions-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectCYP inhibition-
Palavras-chave: dc.subjectCYP2C19-
Palavras-chave: dc.subjectEnantioselective-
Palavras-chave: dc.subjectEthofumesate-
Palavras-chave: dc.subjectHuman liver microsomes-
Palavras-chave: dc.subjectPesticide-drug interaction-
Título: dc.titleEnantioselective inhibition of human CYP2C19 by the chiral pesticide ethofumesate: Prediction of pesticide-drug interactions in humans-
Tipo de arquivo: dc.typelivro digital-
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