Pesticides and their binary combinations as P-glycoprotein inhibitors in NIH 3T3/MDR1 cells

Pivčević, Branka; Žaja, Roko

doi:10.1016/j.etap.2006.04.002

Cited by 33 publications

(30 citation statements)

References 43 publications

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“…It should be however kept in mind that humans are likely exposed not only to a single pyrethroid, but to other pesticides and xenobiotics, that may also interact with drug transporters [55], as recently demonstrated for notably organochlorine pesticides [43], polychlorinated biphenyls [72], diesel exhaust particle components [41] and perfluorinated surfactants [73]. Plasma levels of pyrethroids, especially allethrin and tetramethrin, associated with those of other pollutants, may therefore be sufficient to contribute to synergic or additive inhibitory effects towards drug transporters, as already described for pesticide combinations [74]. In addition, concentrations of pyrethroids may be much higher in the gastro-intestinal tract (before first-pass metabolism) than in plasma, and activities of drug transporters notably expressed at the intestinal level, especially P-gp, MRP2, BCRP, OATP2B1 and OCT1 [22, 75], may therefore be hypothesized to be impacted by ingested pyrethroids.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 91%

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

et al. 2017

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“…In one study the intracellular uptake of the P-gp substrate calcein acetoxymethyl ester in NIH-3T3/ MDR1 cells was measured and both propiconazole and verapamil exhibited similar P-gp inhibition (Pivcevic and Zaja, 2006). However, a second study measuring the cellular efflux of the P-gp substrate doxorubicin in MDR1 expressing B16/10 murine melanoma cells reported that propiconazole inhibited P-gp transport significantly less than verapamil (Bain and LeBlanc,1996).…”

Section: Discussionmentioning

confidence: 94%

“…Previous screening studies evaluating the interaction of propiconazole with P-gp have provided conflicting results (Pivcevic and Zaja, 2006;Bain and LeBlanc, 1996). In one study the intracellular uptake of the P-gp substrate calcein acetoxymethyl ester in NIH-3T3/ MDR1 cells was measured and both propiconazole and verapamil exhibited similar P-gp inhibition (Pivcevic and Zaja, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…To date, limited information exists regarding the interaction of propiconazole with the efflux transporter P-gp and no studies have evaluated its associated metabolites (Pivcevic and Zaja 2006;Bain and LeBlanc 1996). In this study, we investigate the interaction of propiconazole and its hydroxylated metabolites with P-gp using an in vitro P-gp vesicle assay system and human P-gp (MDR1) transfected NIH-3T3 cells.…”

Section: Introductionmentioning

confidence: 99%

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P-glycoprotein inhibition by the agricultural pesticide propiconazole and its hydroxylated metabolites: Implications for pesticide–drug interactions

2015

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“…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 …”

Section: Discussionmentioning

confidence: 99%

Neonicotinoid pesticides poorly interact with human drug transporters

Vée

Bacle

Bruyère

et al. 2019

J Biochem & Molecular Tox

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The interactions of six neonicotinoid pesticides and one neonicotinoid metabolite with drug transporters have been characterized in vitro. Acetamiprid, clothianidin, imidacloprid, nitenpyram, thiacloprid and its metabolite thiacloprid amide, and thiamethoxam, each used at 100 µM, did not impair activity of the efflux pumps P‐glycoprotein, multidrug resistance‐associated proteins, and breast cancer resistance protein. They also did not inhibit that of the uptake transporters OATP1B1, OATP1B3, OAT4, and MATE1, whereas that of OATP2B1, OAT1, and MATE2‐K was affected by only one of the seven neonicotinoids. Activity of OCT1 was moderately stimulated (up to 1.5‐fold) by several neonicotinoids. By contrast, that of OAT3 and OCT2 was inhibited by most (OAT3), if not all (OCT2), neonicotinoids, with IC50 values in the 20 to 60 µM range for thiacloprid, likely not relevant to environmental exposure. Thiacloprid was moreover not transported by OAT3 and OCT2. Overall, these data suggest that neonicotinoid pesticides rather poorly interact with drug transporter activities.

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Pesticides and their binary combinations as P-glycoprotein inhibitors in NIH 3T3/MDR1 cells

Cited by 33 publications

References 43 publications

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

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

P-glycoprotein inhibition by the agricultural pesticide propiconazole and its hydroxylated metabolites: Implications for pesticide–drug interactions

Neonicotinoid pesticides poorly interact with human drug transporters

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