Differential inhibition of AE1 and AE2 anion exchangers by oxonol dyes and by novel polyaminosterol analogs of the shark antibiotic squalamine

Biochem Cell Biol. 1998;76(5):799-806. doi: 10.1139/bcb-76-5-799.

Abstract

Oxonol and polyaminosterol drugs were examined as inhibitors of recombinant mouse AE1 and AE2 anion exchangers expressed in Xenopus laevis oocytes and were compared as inhibitors of AE1-mediated anion flux in red cells and in HL-60 cells that express AE2. The oxonols WW-781, diBA(5)C4, and diBA(3)C4 inhibited HL-60 cell Cl-/Cl- exchange with IC50 values from 1 to 7 microM, 100-1000 times less potent than their IC50 values for red cell Cl-/anion exchange. In Xenopus oocytes, diBA(5)C4 inhibited AE1-mediated Cl- efflux several hundred times more potently than that mediated by AE2. Several novel squalamine-related polyaminosterols were also evaluated as anion exchange inhibitors. In contrast to diBA(5)C4, polyaminosterol 1361 inhibited oocyte-expressed AE2 8-fold more potently than AE1 (IC50 0.6 versus 5.2 microM). The 3-fold less potent desulfo-analog, 1360, showed similar preference for AE2. It was found that 1361 also partially inhibited Cl- efflux from red cells, whereas neither polyaminosterol inhibited Cl efflux from HL60 cells. Thus, the oxonol diBA(5)C4 is >100-fold more potent as an inhibitor of AE1 than of AE2, whereas the polyaminosterols 1360 and 1361 are 8-fold more potent as inhibitors of AE2 than of AE1. Assay conditions and cell type influenced IC50 values for both classes of compounds.

Publication types

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

MeSH terms

  • Animals
  • Anion Transport Proteins*
  • Anti-Bacterial Agents / pharmacology*
  • Antiporters / antagonists & inhibitors*
  • Barbiturates / pharmacology
  • Chloride-Bicarbonate Antiporters
  • Cholestanols / pharmacology
  • Dihydropyridines / pharmacology
  • Dose-Response Relationship, Drug
  • Erythrocytes
  • Fluorescent Dyes / pharmacology*
  • HL-60 Cells
  • Humans
  • Inhibitory Concentration 50
  • Isoxazoles / pharmacology*
  • Kinetics
  • Membrane Proteins / antagonists & inhibitors*
  • Mice
  • Oocytes / metabolism
  • Polyamines / pharmacology*
  • SLC4A Proteins
  • Sharks / metabolism*
  • Xenopus / embryology

Substances

  • Anion Transport Proteins
  • Anti-Bacterial Agents
  • Antiporters
  • Barbiturates
  • Chloride-Bicarbonate Antiporters
  • Cholestanols
  • Dihydropyridines
  • Fluorescent Dyes
  • Isoxazoles
  • KV 1360
  • Membrane Proteins
  • Polyamines
  • SLC4A Proteins
  • bis(1,3-dibutylbarbiturate)trimethine oxonol
  • squalamine