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In vitro enantioselective study of the toxicokinetic effects of chiral fungicide tebuconazole in human liver microsomes.
Habenschus, Maísa Daniela; Nardini, Viviani; Dias, Luís Gustavo; Rocha, Bruno Alves; Barbosa, Fernando; de Oliveira, Anderson Rodrigo Moraes.
Afiliação
  • Habenschus MD; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901, Ribeirão Preto, SP, Brazil.
  • Nardini V; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901, Ribeirão Preto, SP, Brazil.
  • Dias LG; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901, Ribeirão Preto, SP, Brazil.
  • Rocha BA; Laboratório de Toxicologia e Essencialidade de Metais, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14049-903, Ribeirão Preto, SP, Brazil.
  • Barbosa F; Laboratório de Toxicologia e Essencialidade de Metais, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14049-903, Ribeirão Preto, SP, Brazil.
  • de Oliveira ARM; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901, Ribeirão Preto, SP, Brazil. Electronic address: deoliveira@usp.br.
Ecotoxicol Environ Saf ; 181: 96-105, 2019 Oct 15.
Article em En | MEDLINE | ID: mdl-31176252
Tebuconazole (TEB) is a chiral triazole fungicide that is globally marketed and used as a racemic mixture to control plant pathogens. Due to its use as a racemic mixture, TEB may exhibit enantioselective toxicokinetics toward nontarget organisms, including humans. Therefore, the in vitro enantioselective metabolism of TEB by cytochrome P450 enzymes (CYP450) was studied using human liver microsomes, and the in vivo toxicokinetic parameters were predicted. A new enantioselective, reversed-phase LC-MS/MS method was developed and validated to analyze the enantiomers of TEB and its main metabolite, 1-hydroxytebuconazole (TEBOH). In vitro metabolic parameters were obtained, and in vitro-in vivo extrapolations were performed. Michaelis-Menten and atypical biphasic kinetic profiles were observed with a total intrinsic clearance ranging from 53 to 19 mL min-1 mg-1. The in vitro-in vivo extrapolation results showed that TEB first passage effect by the liver seems to be negligible, with hepatic clearance and extraction ratios ranging from 0.53 to 5.0 mL min-1 kg-1 and 2.7-25%, respectively. Preferential metabolism of (+)-TEB to rac-TEB and (-)-TEB was observed, with preferential production of (+)-TEBOH. Furthermore, reaction phenotyping studies revealed that, despite the low hepatic clearance in the first pass metabolism of TEB, multiple human CYP450 isoforms were involved in TEB metabolism when TEBOH enantiomers were generated, mainly CYP3A4 and CYP2C9, which makes TEB accumulation in the human body more difficult due to multiple metabolic pathways.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Triazóis / Microssomos Hepáticos / Fungicidas Industriais Limite: Humans Idioma: En Revista: Ecotoxicol Environ Saf Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Triazóis / Microssomos Hepáticos / Fungicidas Industriais Limite: Humans Idioma: En Revista: Ecotoxicol Environ Saf Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda