Interactions of pesticides with membrane drug transporters: implications for toxicokinetics and toxicity

ABSTRACT

Introduction: Drug transporters are now recognized as major actors of pharmacokinetics. They are also likely implicated in toxicokinetics and toxicology of environmental pollutants, notably pesticides, to which humans are widely exposed and which are known to exert various deleterious effects toward health. Interactions of pesticides with drug transporters are therefore important to consider.

Areas covered: This review provides an overview of the interactions of pesticides with membrane drug transporters, i.e. inhibition of their activity, regulation of their expression, and handling of pesticides. Consequences for toxicokinetics and toxicity of pesticides are additionally summarized and discussed.

Expert opinion: Some pesticides belonging to several chemical classes, such as organochlorine, pyrethroid, and organophosphorus pesticides, have been demonstrated to interact with various uptake and efflux drug transporters, including the efflux pump P-glycoprotein (P-gp) and the uptake organic cation transporters (OCTs). This provides proof of the concept that pesticide–transporter relationships merit attention. More extensive and systematic characterization of pesticide–transporter relationships, possibly through the use of in silico methods, is however likely required. In addition, consideration of transporter polymorphisms, pesticide mixture effects, and realistic pesticide concentrations reached in humans may help better define the in vivo relevance of pesticide–transporter interactions in terms of toxicokinetics and toxicity.

KEYWORDS:

• Drug transporters
• environmental exposure
• pesticides
• toxicity
• toxicokinetics

Article highlights

• Interactions of organic pesticides with drug transporters are important to consider owing to the major contribution of transporters to toxicokinetics and the well-established toxic effects of pesticides, to which humans are widely exposed.

• Various pesticides belonging to diverse chemical classes, including organochlorine, pyrethroid, and organophosphorus pesticides, can inhibit the activity of ATP-binding cassette or SLC drug transporters. Activities of the drug efflux pump P-gp and of the uptake transporters OCT1 and OCT2 have notably been demonstrated to be impacted by pesticides.

• Concentrations of pesticides that block in vitro transporter activities (in the 1–100 µM range) are commonly much higher than those reached in humans in response to environmental exposure, making the in vivo relevance of transporter inhibition unlikely for most of the pesticides.

• A limited number of pesticides have been shown to regulate the expression of some drug transporters, notably in hepatic cells.

• Pesticides can additionally be substrates for drug transporters, which may contribute to their toxicokinetics and may also govern their toxicity.

• Overall, pesticides remain poorly characterized with respect to relationships with transporters. A more extensive and systematic characterization of the interactions of pesticides with drug transporters is consequently required. Polymorphisms in transporters, pesticide mixture effects, and the interplay between transporters and drug metabolizing enzymes constitute additional issues that warrant attention.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer declaration of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.