title: P-glycoprotein inhibition by the agricultural pesticide propiconazole and its hydroxylated metabolites: Implications for pesticide-drug interactions.
abstract: 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 (IC50,122.9μM) and its metabolites (IC50s, 350.8μM, 366.4μM, and 456.3μM) 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 10μM) 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.
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Ecosystems Research Division, 960 College Station Road, Athens, GA 30605, USA. Electronic address: mazur.chris@epa.gov.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Mazur
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Ecosystems Research Division, 960 College Station Road, Athens, GA 30605, USA. Electronic address: marchitti.satori@epa.gov.
authors.forename: Satori A
authors.initials: SA
authors.lastname: Marchitti
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA. Electronic address: jzastre@uga.edu.
authors.forename: Jason
authors.initials: J
authors.lastname: Zastre
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006900:Hydroxylation; D051379:Mice; D041681:NIH 3T3 Cells; D017239:Paclitaxel / Q000378:metabolism / Q000633:toxicity; D010575:Pesticides / Q000378:metabolism / Q000633:toxicity*; D018570:Risk Assessment; D014162:Transfection; D014230:Triazoles / Q000378:metabolism / Q000633:toxicity*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D010575:Pesticides; D014230:Triazoles; C045950:propiconazole; D017239:Paclitaxel
keywords: ABC transporters; Chemosensitization; Conazoles; MDR1; P-gp; Propiconazole