title: Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein.
abstract: The multixenobiotic resistance phenotype is characterized by the reduced accumulation of xenobiotics by cells or organisms due to increased efflux of the compounds by P-glycoprotein (P-gp) or related transporters. An extensive xenobiotic database, consisting primarily of pesticides, was utilized in this study to identify molecular characteristics that render a xenobiotic susceptible to transport by or inhibition of P-gp. Transport substrates were differentiated by several molecular size/shape parameters, lipophilicity, and hydrogen bonding potential. Electrostatic features differentiated inhibitory ligands from compounds not catagorized as transport substrates and that did no interact with P-gp. A two-tiered system was developed using the derived structure-activity relationships to identify P-gp transport substrates and inhibitory ligands. Prediction accuracy of the approach was 82%. We then validated the system using six additional pesticides of which tow were predicted to be P-gp inhibitors and four were predicted to be noninteractors, based upon the structure-activity analyses. Experimental determinations using cells transfected with the human MDR1 gene demonstrated that five of the six pesticides were properly catagorized by the structure-activity analyses (83% accuracy). Finally, structure-activity analyses revealed that among P-gp inhibitors, relative inhibitory potency can be predicted based upon the surface area or volume of the compound. These results demonstrate that P-gp transport substrates and inhibitory ligands can be distinguished using molecular characteristics. Molecular characteristics of transport substrates suggest that P-gp may function in the elimination of hydroxylated metabolites of xenobiotics.
authors.affiliation: Department of Toxicology, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bain
authors.forename: J B
authors.initials: JB
authors.lastname: McLachlan
authors.forename: G A
authors.initials: GA
authors.lastname: LeBlanc
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019450:Genes, MDR; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008546:Melanoma, Experimental; D010575:Pesticides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008024:Ligands; D010575:Pesticides; D015262:Xenobiotics