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Keywords:

  • astrocytes;
  • brain;
  • glutathione disulfide export;
  • glutathione transport;
  • multidrug resistance proteins;
  • oxidative stress

Abstract

Astrocytes play an important role in the glutathione (GSH) metabolism of the brain. To test for an involvement of multidrug resistance protein (Mrp) 1 and 5 in the release of GSH and glutathione disulfide (GSSG) from astrocytes, we used astrocyte cultures from wild-type, Mrp1-deficient [Mrp1(–/–)] and Mrp5-deficient [Mrp5(–/–)] mice. During incubation of wild-type or Mrp5(–/–) astrocytes, GSH accumulated in the medium at a rate of about 3 nmol/(h.mg), whereas the export of GSH from Mrp1(–/–) astrocytes was only one-third of that. In addition, Mrp1(–/–) astrocytes had a 50% higher specific GSH content than wild-type or Mrp5(–/–) cells. The presence of 50 μm of the Mrp inhibitor MK571 inhibited the rate of GSH release from wild-type and Mrp5(–/–) astrocytes by 60%, but stimulated at the low concentration of 1 μm GSH release by 40%. In contrast, both concentrations of MK571 did not affect GSH export from Mrp1(–/–) astrocytes. Moreover, in contrast to wild-type and Mrp5(–/–) cells, GSSG export during H2O2 stress was not observed for Mrp1(–/–) astrocytes. These data demonstrate that in astrocytes Mrp1 mediates 60% of the GSH export, that Mrp1 is exclusively responsible for GSSG export and that Mrp5 does not contribute to these transport processes.