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

Autor(es)

Habenschus, Maisa Daniela ^[1] ; Carrao, Daniel Blascke ^[1] ; Perez de Albuquerque, Nayara Cristina ^[1] ; Perovani, Icaro Salgado ^[1] ; da Silva, Rodrigo Moreira ^[2] ; Nardini, Viviani ^[1] ; Lopes, Norberto Peporine ^[2] ; Dias, Luis Gustavo ^[1] ; Moraes de Oliveira, Anderson Rodrigo ^{[1, 3]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, Av Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, BR-14090903 Ribeirao Preto, SP - Brazil

^[3] Natl Inst Alternat Technol Detect Toxicol Evaluat, Inst Chem, UNESP, POB 355, BR-14800900 Araraquara, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Toxicology Letters; v. 351, p. 1-9, OCT 15 2021.
• Citações Web of Science: 0

Resumo

Tebuconazole (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 (K-i = 1.3 +/- 0.3 mu M, alpha K-i = 3.2 +/- 0.5 mu M; K-i = 0.6 +/- 0.3 mu M, alpha K-i = 1.3 +/- 0.3 mu M) and CYP2C9 (K-i = 0.7 +/- 0.1 mu M, alpha K-i = 2.7 +/- 0.5 mu M), and a competitive inhibitor of CYP2D6 (K-i = 11.9 +/- 0.7 mu M) and CYP2C19 (K-i = 0.23 +/- 0.02 mu M), 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. 2021 Elsevier B.V. All rights reserved. (AU)

• 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
• Processo FAPESP: 18/07534-4 - Desenvolvimento de métodos cromatográficos/eletroforéticos para posterior aplicação em estudos in vitro de inibição enzimática e predição de interações medicamentosas de praguicidas quirais - Fase 2
• Beneficiário: Anderson Rodrigo Moraes de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/03204-7 - Desenvolvimento e aplicação de campo de força coarse-graining em sistemas auto-organizados
• Beneficiário: Luis Gustavo Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular