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Structure-Activity Relationships for Xenobiotic Transport Substrates and Inhibitory Ligands of P-glycoprotein
Lisa J. Bain, James B. McLachlan, and Gerald A. LeBlanc
Department of Toxicology, North Carolina State University, Raleigh, NC 27695 USA
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 not 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 two 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.
Key words
: multidrug resistance, multixenobiotic resistance, pesticides, P-glycoprotein, structure-activity relationships.
Environ Health Perspect
105:812-818 (1997)
Address correspondence to G.A. LeBlanc, Department of Toxicology, North Carolina State University, Box 7633, Raleigh, NC 27695 USA.
This work was supported by NIEHS grant PO1 ES-00044.
