Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

Abstract

Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 μM (OCT1 inhibition by allethrin) to 77.6 μM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 μM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.

Neonicotinoid pesticides poorly interact with human drug 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 …”

“…Breast cancer resistance protein (BCRP/ ABCG2 )‐transfected HEK293 cells (HEK‐BCRP cells), kindly donated by Pr X. Decleves (Faculty of Pharmacy, University Paris‐Descartes, Paris, France), were cultured in DMEM supplemented with 10% (vol/vol) fetal calf serum, 100 IU/mL amoxicillin, 100 μg/mL erythromycin, and 2,000 μg/mL G418. HEK293 cells overexpressing organic anion transporter polypeptide (OATP/ SCLO ) 1B1/ SLCO1B1 (HEK‐OATP1B1 cells), OATP1B3/ SLCO1B3 (HEK‐OATP1B3 cells), OATP2B1/ SLCO2B 1 (HEK‐OATP2B1 cells), organic anion transporter (OAT) 1/ SLC22A6 (HEK‐OAT1 cells), OAT3/ SLC22A8 (HEK‐OAT3 cells), OAT4/ SLC22A11 (HEK‐OAT4 cells), organic cation transporter (OCT) 1/ SLC22A1 (HEK‐OCT1 cells), OCT2/ SLC22A2 (HEK‐OCT2 cells), multidrug and toxin extrusion protein (MATE) 1/ SLC47A1 (HEK‐MATE1 cells) or MATE2‐K/ SLC47A2 (HEK‐MATE2‐K cells) were generated by transduction of HEK293 cells with the appropriate lentiviral drug transporter vectors . Control HEK293 cells (HEK‐MOCK cells) were obtained in parallel by transduction of an empty lentiviral vector.…”

“…Monitored ion transition for TEA was at 130.2 greater than 86.1 m/z. Substrate amount values were finally normalized to cellular protein content determined by the Bradford method, as previously reported …”

“…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

“…ABC transporters may be additionally targeted; fenamiphos thus blocks P‐gp (Table S1). Some pesticides can stimulate the activity of SLC transporters, thus illustrating the multifaceted features of pesticide‐transporter interactions; for example, allethrin and tetramethrin enhance the activity of OATP2B1 …”