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

被引：31
作者：
Carrao, Daniel Blascke [1 ]
Habenchus, Maisa Daniela [1 ]
Perez de Albuquerque, Nayara Cristina [1 ]
da Silva, Rodrigo Moreira [2 ]
Lopes, Norberto Peporine [2 ]
Moraes de Oliveira, Anderson Rodrigo [1 ,3 ]
机构：
[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] UNESP, Inst Chem, Natl Inst Alternat Technol Detect Toxicol Evaluat, POB 355, BR-14800900 Araraquara, SP, Brazil
来源：
TOXICOLOGY LETTERS | 2019年 / 313卷
基金：
巴西圣保罗研究基金会;
关键词：
Fipronil; Fipronil sulfone; Cytochrome P450; Pesticide-drug interaction; Inhibition mechanism; In vitro; Human liver microsomes; HUMAN CYTOCHROME-P450 ENZYMES; NEONICOTINOIDS; ENANTIOMERS; RISK; RAT;
D O I：
10.1016/j.toxlet.2019.07.005
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
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.
引用
收藏
页码：196 / 204
页数：9
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