An evaluation of the cytochrome P450 inhibition potential of selected pesticides in human hepatic microsomes

Abstract

The goal of this work was to study the ability of 18 pesticides to inhibit selective model activities for all major xenobiotic-metabolizing enzymes, namely CYP1A1/2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Generally organophosphorus insecticides were the most potent and extensive inhibitors, especially towards CYP1A1/2 (IC₅₀ values of chlorpyrifos, fenitrothion and profenofos ∼3 μ M), CYP2B6 (IC₅₀ values of chlorpyrifos and fenitrothion 2.5 μ M), CYP2C8 (fenitrothion 4.3 μ M), CYP2C9 (fenitrothion and malathion 4.8 and 2.5 μ M, respectively), CYP2D6 (chlorpyrifos and phenthoate ∼ 3 μ M) and CYP3A4 (chlorpyrifos, fenitrothion and phenthoate 3–4 μ M). Otherwise there were quite considerable differences in potency and extent of inhibition between different organophosphates. Pyrethroids were in general very weak or inactive. Deltamethrin and fenvalerate were potent inhibitors of CYP2D6 (IC₅₀ values of ∼ 3 μ M) while lambda-cyhalothrin potently inhibited both CYP2D6 and CYP3A4-mediated activities (IC₅₀'s about 3–4 μ M). Some pesticides caused relatively potent inhibitions sporadically (carbendazim, CYP2D6, IC₅₀ = 12 μ M; atrazine, CYP3A4, IC₅₀ = 2.8 μ M; glyphosate, CYP2C9, IC₅₀ = 3.7 μ M; hexaflumuron, IC₅₀ = 6.0 μ M). With the exceptions of alpha-cypermethrin, cypermethrin, isoproturon, carbaryl and abamectin, most pesticides inhibited relatively potently at least one CYP-selective activity, which may have relevance for potential interactions in occupational exposures and for further studies on the CYP-associated metabolism of respective pesticides.

Keywords:

• Pesticides
• inhibitory interactions
• P450
• human liver microsomes
• in vitro

Acknowledgments

The technical assistance of Ritva Tauriainen is gratefully acknowledged. This work was funded by the Ministry of Education-supported position from Finnish Graduate School in Toxicology (ToxGS) and by grants from The Academy of Finland and The Finnish Granting Agency for Technological Research and Innovation (TEKES) and supported by grants from Oulu University Scholarship Foundation and the Agriculture Foundation of Economic Association in the Oulu province.

Notes

¹The incubation conditions to assess CYP enzyme activities and analysis conditions are mentioned in detail in our previous publication. ^{[ 14 ]}

²Midazolam 1′-hydroxylation.

³Omeprazole sulfoxidation.

¹Midazolam 1′-hydroxylation.

²Omeprazole sulfoxidation.