title: Inhibition of MRP1-mediated efflux in human erythrocytes by mono-anionic bile salts.
abstract: BACKGROUND
  Multidrug resistance-associated protein 1 (MRP1 or ABCC1) -mediated transport is an important mechanism in multidrug resistance during cancer treatment. One strategy for the reversal of MRP1-mediated multidrug resistance is inhibition of this efflux pump. Therefore, efficient inhibitors are searched for and the structure-activity relationships of inhibitors are studied. In the present work, the ability of a series of mono-anionic bile salts to inhibit MRP1-like substrate transport was examined.
  
  
  METHODS
  The effect of bile salts on the efflux of the MRP1 substrate 2,7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes was fluorimetrically monitored.
  
  
  RESULTS
  All bile salts inhibited the BCPCF efflux. The most efficient inhibitor, lithocholic acid, decreased the BCPCF efflux by 50% (IC50) at 4 microM during 60 min of incubation at 37 degrees C. The most efficient bile salt inhibitors showed high haemolysis start/IC50 concentration ratios and did not induce membrane bending or phosphatidylserine (PS) exposure at IC50.
  
  
  CONCLUSIONS
  The overall hydrophobicity, as well as the orientation of the hydroxyl groups and conjugation with glycine or taurine per se, affect the inhibitory potency of bile salts. The most efficient inhibitors apparently interact with MRP1 in a specific way.
authors.affiliation: Department of Cytology and Histology, A. Mickiewicz University, PL-61701 Poznan, Poland.
authors.forename: Lucyna
authors.initials: L
authors.lastname: Mrówczynska
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bobrowska-Hägerstrand
authors.forename: Anna
authors.initials: A
authors.lastname: Wróbel
authors.forename: Thomas
authors.initials: T
authors.lastname: Söderström
authors.forename: Henry
authors.initials: H
authors.lastname: Hägerstrand
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D000838:Anions; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005452:Fluoresceins / Q000493:pharmacokinetics; D005470:Fluorometry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D010718:Phosphatidylserines / Q000097:blood
chemical_list: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D001457:Anion Exchange Protein 1, Erythrocyte; D000838:Anions; D001647:Bile Acids and Salts; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010718:Phosphatidylserines; C473073:2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein; C454201:SLC4A1 protein, human; C421109:multidrug resistance-associated protein 1