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

•Propiconazole and CYP450 metabolites inhibited P-gp transport in membrane vesicles.•Propiconazole acts as an inhibitor of P-gp rather than a substrate.•Propiconazole chemosensitized NIH-3T3/MDR1 cells to the P-gp substrate paclitaxel.•P-gp inhibition by propiconazole may influence cellular pesticide-drug interactions.

The human efflux transporter P-glycoprotein (P-gp, MDR1) functions as an important cellular defense system against a variety of xenobiotics; however, little information exists on whether environmental chemicals interact with P-gp. Conazoles provide a unique challenge to exposure assessment because of their use as both pesticides and drugs. Propiconazole is an agricultural pesticide undergoing evaluation by the U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program. In this study, the P-gp interaction of propiconazole and its hydroxylated metabolites were evaluated using MDR1-expressing membrane vesicles and NIH-3T3/MDR1 cells. Membrane vesicle assays demonstrated propiconazole (IC50,122.9 μM) and its metabolites (IC50s, 350.8 μM, 366.4 μM, and 456.3 μM) inhibited P-gp efflux of a probe substrate, with propiconazole demonstrating the strongest interaction. P-gp mediated transport of propiconazole in MDR1-expressed vesicles was not detected indicating propiconazole interacts with P-gp as an inhibitor rather than a substrate. In NIH-3T3/MDR1 cells, propiconazole (1 and 10 μM) led to decreased cellular resistance (chemosensitization) to paclitaxel, a chemotherapeutic drug and known MDR1 substrate. Collectively, these results have pharmacokinetic and risk assessment implications as P-gp interaction may influence pesticide toxicity and the potential for pesticide-drug interactions.