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Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications

[ Vol. 8 , Issue. 6 ]

Author(s):

Ferenc Zsila   Pages 563 - 593 ( 31 )

Abstract:


Plasma α1-acid glycoprotein (AGP) is an important modulator of drug disposition, since it binds and transports of a vast array of pharmaceutical agents. The ABC transporter efflux pump, P-glycoprotein (P-gp), also recognizes and binds a broad range of weakly basic and uncharged xenobiotics. Its efflux activity plays a key role in pharmacokinetics of drugs, and overexpression of P-gp in malignant cells confers multidrug resistance (MDR) to anticancer agents. Comparison of ligand specificities of AGP and P-gp revealed high similarity showing that both proteins interact with the same therapeutic classes of drugs (α/β-blockers, anticancer agents, Ca2+ antagonists, antipsychotics/neuroleptics, HIV protease inhibitors etc.) as well as with additional endo- and exogenous compounds (steroids, dyes, natural substances). A wealth of examples are presented to show the potential use of drug-AGP binding data to predict drug-P-gp interactions and vice versa. In addition, structural and functional similarities between AGP and P-gp have been highlighted. Based on these data, several proposals have been made: 1) AGP and P-gp might act synergistically in protecting cells from harmful xenobiotics; 2) An extensive shared list of their ligands allows prediction of mutual binding interactions; 3) Interaction of drugs and drug candidates, both with AGP and P-gp, should be considered to optimize pharmacotherapy and to delineate the causes of drug-drug interactions; 4) Structures of known AGP binders could be exploited in searching for novel scaffolds of P-gp modulators to overcome cancer MDR and efflux-mediated resistance in microorganisms and parasites; 5) Novel fluorescent probes for studying P-gp structure and function can be pre-selected among AGP binder agents.

Keywords:

ABC transporters, Human serum α1-acid glycoprotein, Drug-binding, Drug-transport, Multidrug resistance, P-glycoprotein, Substrate specificity

Affiliation:

Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, H-1525, Budapest, P.O. Box 17, Hungary.



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