title: Interaction of structurally diverse pesticides with the human MDR1 gene product P-glycoprotein.
abstract: P-glycoprotein (P-gp) is a 170-kDa membrane-bound glycoprotein shown to efflux a wide variety of chemicals, such as chemotherapeutic agents and carcinogens. Experiments were conducted using B16/F10 murine melanoma cells transfected with the human MDR1 gene (B16/hMDR1 cells), which codes for P-gp, to determine whether this transporter may contribute to the cellular efflux of some pesticides. Thirty-eight pesticides representing several classes of compounds were evaluated for their potential to bind to P-gp, as measured by the inhibition of efflux of the P-gp substrate doxorubicin. Carbamate and pyrethroid insecticides exhibited little interaction with P-gp, while many of the organophosphorus and organochlorine pesticides significantly inhibited the efflux of doxorubicin. Pesticides that significantly inhibited the efflux of doxorubicin were then assessed for P-gp-mediated efflux. One pesticide, endosulfan, exhibited slight though significant transport mediated by P-gp. Competition experiments performed with the P-glycoprotein ligand [3H]azidopine demonstrated that the P-gp inhibitory pesticides bound to P-gp. Both lipophilicity and molecular mass were major physical/chemical determinants in dictating pesticide binding to P-gp, with optimum binding occurring with compounds having a log Kow value of 3.6-4.5 and a molecular weight of 391-490 Da. The transport substrate endosulfan possessed optimal binding characteristics. These results demonstrated that many pesticides are capable of binding to P-gp; however, binding does not infer transport.
authors.affiliation: Department of Toxicology, North Carolina State University, Raleigh 27695, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bain
authors.forename: G A
authors.initials: GA
authors.lastname: LeBlanc
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010575:Pesticides / Q000378:metabolism* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010575:Pesticides; D004317:Doxorubicin