Interactions of organophosphorus pesticides with solute carrier (SLC) drug transporters

Abstract

1. Organophosphorus pesticides (OPs) are known to interact with human ATP-binding cassette drug efflux pumps. The present study was designed to determine whether they can also target activities of human solute carrier (SLC) drug transporters.

2. The interactions of 13 OPs with SLC transporters involved in drug disposition, such as organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs), were mainly investigated using transporter-overexpressing cell clones and fluorescent or radiolabeled reference substrates.

3. With a cut-off value of at least 50% modulation of transporter activity by 100 µM OPs, OAT1 and MATE2-K were not impacted, whereas OATP1B1 and MATE1 were inhibited by two and three OPs, respectively. OAT3 activity was similarly blocked by three OPs, and was additionally stimulated by one OP. Five OPs cis-stimulated OATP2B1 activity. Both OCT1 and OCT2 were inhibited by the same eight OPs, including fenamiphos and phosmet, with IC₅₀ values however in the 3–30 µM range, likely not relevant to environmental exposure.

4. These data demonstrated that various OPs inhibit SLC drug transporter activities, especially those of OCT1 and OCT2, but only when used at high concentrations not expected to occur in environmentally-exposed humans.

Keywords:

• Organophosphorus pesticide
• drug transporter
• solute carrier
• dopamine
• molecular descriptors
• organic cation transporters
• SLC transporters

Acknowledgements

We thank Dr D. Mias-Lucquin for his kind help for statistical analysis of molecular descriptor data and Dr Y. Parmentier and Dr C. Denizot for helpful support with HEK293 cell clones overexpressing transporters. The authors also acknowledge the Centre de Ressources Biologiques (CRB) Santé of Rennes BB-0033-00056 for managing hepatocyte supply and Technologie Servier (Orléans, France) for the gift of the LC-MS/MS system.

Disclosure statement

No potential conflict of interest was reported by the authors.