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

Author(s)

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]}

Affiliation

^[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

• Document type: Journal article
• Source: Toxicology Letters; v. 351, p. 1-9, OCT 15 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 14/50945-4 - INCT 2014: National Institute for Alternative Technologies of Detection, Toxicological Evaluation and Removal of Micropollutants and Radioactivies
• Grantee: Maria Valnice Boldrin
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/07534-4 - Development of chromatographic / electrophoretic methods to be further applied in in vitro enzymatic inhibition studies and prediction of drug interactions of chiral pesticides - Phase 2
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/03204-7 - Development and application of coarse-graining force field in self-assembled systems
• Grantee: Luis Gustavo Dias
• Support Opportunities: Regular Research Grants