Overlapping ligand specificity of P-glycoprotein and serum alpha(1)-acid glycoprotein: evidences and potential implications.
Plasma alpha(1)-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 (alpha/beta-blockers, anticancer agents, Ca(2+) 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.
Zsila
Ferenc
F
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Budapest, Hungary. zsferi@chemres.hu
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009961:Orosomucoid / Q000737:chemistry / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008024:Ligands; D009961:Orosomucoid; D051544:Cytochrome P-450 CYP3A