Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein

Environ Health Perspect. 1997 Aug;105(8):812-8. doi: 10.1289/ehp.97105812.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Carrier Proteins / metabolism
  • Drug Resistance, Multiple / physiology*
  • Genes, MDR
  • Humans
  • In Vitro Techniques
  • Ligands
  • Melanoma, Experimental
  • Pesticides / pharmacology*
  • Structure-Activity Relationship
  • Transfection
  • Xenobiotics / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carrier Proteins
  • Ligands
  • Pesticides
  • Xenobiotics