In vitro inhibition of human CYP2D6 by the chiral pesticide fipronil and its metabolite fipronil sulfone: Prediction of pesticide-drug interactions

[Display omitted] •Rac-fipronil, S-fipronil, R-fipronil and fipronil sulfone inhibited CYP2D6.•Both fipronil and its metabolite are competitive inhibitors of CYP2D6.•No enantioselective enzyme inhibition of CYP2D6 was observed.•Rac-fipronil, S-fipronil, R-fipronil are moderate inhibitors of CYP2D6.•...

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Bibliographic Details
Published in:Toxicology letters 2019-10, Vol.313, p.196-204
Main Authors: Carrão, Daniel Blascke, Habenchus, Maísa Daniela, de Albuquerque, Nayara Cristina Perez, da Silva, Rodrigo Moreira, Lopes, Norberto Peporine, de Oliveira, Anderson Rodrigo Moraes
Format: Article
Language:English
Subjects:
Cytochrome P450
Fipronil
Fipronil sulfone
Human liver microsomes
In vitro
Inhibition mechanism
Pesticide-drug interaction
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Summary:[Display omitted] •Rac-fipronil, S-fipronil, R-fipronil and fipronil sulfone inhibited CYP2D6.•Both fipronil and its metabolite are competitive inhibitors of CYP2D6.•No enantioselective enzyme inhibition of CYP2D6 was observed.•Rac-fipronil, S-fipronil, R-fipronil are moderate inhibitors of CYP2D6.•Fipronil sulfone is a strong inhibitor of CYP2D6. Fipronil is a chiral insecticide employed worldwide in crops, control of public hygiene and control of veterinary pests. Humans can be exposed to fipronil through occupational, food, and environmental contamination. Therefore, the risk assessment of fipronil in humans is important to protect human health. Fipronil sulfone is the major metabolite formed during fipronil metabolism by humans. Since the CYP450 enzymes are the main ones involved in drug metabolism, the evaluation of their inhibition by fipronil and its main metabolite is important to predict drug-pesticide interactions. The aim of this work was to investigate the inhibition effects of rac-fipronil, S-fipronil, R-fipronil and fipronil sulfone on the main human CYP450 isoforms. The results showed that CYP2D6 is the only CYP450 isoform inhibited by these xenobiotics. In addition, no enantioselective differences were observed in the inhibition of CYP450 isoforms by fipronil and its individuals’ enantiomers. Rac-fipronil, S-fipronil and R-fipronil are moderate CYP2D6 inhibitors showing a competitive inhibition profile. On the other hand, the metabolite fipronil sulfone showed to be a strong inhibitor of CYP2D6 also by competitive inhibition. These results highlight the importance of metabolite evaluation on pesticide safety since the metabolism of fipronil into fipronil sulfone increases the risk of pesticide-drug interactions for drugs metabolized by CYP2D6.
ISSN:0378-4274
1879-3169
DOI:10.1016/j.toxlet.2019.07.005