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 IC 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.

Neonicotinoid pesticides poorly interact with human drug transporters

“…OCT1 activity was nevertheless cis ‐stimulated by several neonicotinoids, in a rather moderate manner ( cis ‐stimulation by a maximum of 1.5‐fold factor for thiacloprid). A cis ‐stimulation of SLC transporter activity by pesticides also occurs for some organophosphorus pesticides . Some marketed drugs can similarly cis ‐stimulate activities of SLC transporters .…”

“…Inhibition of OAT3 and OCT2 activities is thus unlikely to occur in humans environmentally exposed to neonicotinoid pesticides. In the same manner, inhibitions of drug transporters by organochlorine, pyrethroid, or organophosphorus pesticides are observed in vitro for concentrations higher than those found in the environment . Putative synergistic inhibitory effects of pesticide mixtures toward transporters, however, have to be considered for judging the potential relevance of transporter‐pesticide interactions …”

“…Besides drugs, environmental pollutants, including pesticides, interact with drug transporters, thus underlining interest in studying potential transporter‐chemical interactions in an extensive and detailed manner . Some pyrethroid insecticides, organophosphorus compounds or organochlorine pesticides thus inhibit activity of ABC and/or SLC drug transporters, whereas other pesticides, like the insecticide methoxychlor or the herbicide 2,4‐dichlorophenoxyacetic acid are substrates for transporters.…”

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

“…It is noteworthy that some pesticides decrease membrane transport of endogenous substrates for SLC transporters in in vitro models. Some organophosphorus and pyrethroid pesticides thus inhibit OCT1‐mediated transport of dopamine . This alteration of dopaminergic pathways might contribute to Parkinson's disease, for which exposure to pesticides is suspected to be a risk factor .…”

“…Mixtures of pesticides should be considered because the inhibitory effects of agrochemicals towards transporters can be synergistic. Thus, inhibition of P‐gp activity by binary mixtures of diazinon and other pesticides is synergistic, as well as that of OCT2 by the organophosphorous pesticides phosmet and fenamiphos . It is noteworthy that such transporter inhibitions by mixtures of pesticides, in contrast to those due to a single pesticide, can be relevant for realistic exposure conditions because humans are commonly exposed to mixtures of pesticides.…”