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Titolo:
STRUCTURE-ACTIVITY-RELATIONSHIPS FOR XENOBIOTIC TRANSPORT SUBSTRATES AND INHIBITORY LIGANDS OF P-GLYCOPROTEIN
Autore:
BAIN LJ; MCLACHLAN JB; LEBLANC GA;
Indirizzi:
N CAROLINA STATE UNIV,DEPT TOXICOL,BOX 7633 RALEIGH NC 27695 N CAROLINA STATE UNIV,DEPT TOXICOL RALEIGH NC 27695
Titolo Testata:
Environmental health perspectives
fascicolo: 8, volume: 105, anno: 1997,
pagine: 812 - 818
SICI:
0091-6765(1997)105:8<812:SFXTSA>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERFORMANCE LIQUID-CHROMATOGRAPHY; MULTIDRUG-RESISTANCE; GENE LEADS; CELLS; DRUGS; PESTICIDES; PROGESTERONE; VINCRISTINE; DISRUPTION; VERAPAMIL;
Keywords:
MULTIDRUG RESISTANCE; MULTIXENOBIOTIC RESISTANCE; PESTICIDES; P-GLYCOPROTEIN; STRUCTURE-ACTIVITY RELATIONSHIPS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
35
Recensione:
Indirizzi per estratti:
Citazione:
L.J. Bain et al., "STRUCTURE-ACTIVITY-RELATIONSHIPS FOR XENOBIOTIC TRANSPORT SUBSTRATES AND INHIBITORY LIGANDS OF P-GLYCOPROTEIN", Environmental health perspectives, 105(8), 1997, pp. 812-818

Abstract

The multixenobiotic resistance phenotype is characterized by the reduced accumulation of xenobiotics by cells or organisms due to increasedefflux 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 withP-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 potencycan 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 if xenobiotics.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 13:08:09