Glutathione transport is a unique function of the ATP-binding cassette protein ABCG2

J Biol Chem. 2010 May 28;285(22):16582-7. doi: 10.1074/jbc.M109.090506. Epub 2010 Mar 23.

Abstract

Glutathione (GSH) transport is vital for maintenance of intracellular and extracellular redox balance. Only a few human proteins have been identified as transporters of GSH, glutathione disulfide (GSSG) and/or GSH conjugates (GS-X). Human epithelial MDA1586, A549, H1975, H460, HN4, and H157 cell lines were exposed to 2',5'-dihydroxychalcone, which induces a GSH efflux response. A real-time gene superarray for 84 proteins found in families that have a known role in GSH, GSSG, and/or GS-X transport was employed to help identify potential GSH transporters. ABCG2 was identified as the only gene in the array that closely corresponded with the magnitude of 2',5'-dihydroxychalcone (2',5'-DHC)-induced GSH efflux. The role of human ABCG2 as a novel GSH transporter was verified in a Saccharomyces cerevisiae galactose-inducible gene expression system. Yeast expressing human ABCG2 had 2.5-fold more extracellular GSH compared with those not expressing ABCG2. GSH efflux in ABCG2-expressing yeast was abolished by the ABCG2 substrate methotrexate (10 microM), indicating competitive inhibition. In contrast, 2',5'-DHC treatment of ABCG2-expressing yeast increased extracellular GSH levels in a dose-dependent manner with a maximum 3.5-fold increase in GSH after 24 h. In addition, suppression of ABCG2 with short hairpin RNA or ABCG2 overexpression in human epithelial cells decreased or increased extracellular GSH levels, respectively. Our data indicate that ABCG2 is a novel GSH transporter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / chemistry*
  • Amino Acids / chemistry
  • Antioxidants / metabolism
  • Biological Transport
  • Carrier Proteins / chemistry*
  • Cell Line, Tumor
  • Chalcones / chemistry
  • Fungal Proteins / metabolism
  • Gene Expression Regulation*
  • Glutathione / metabolism*
  • Humans
  • Models, Biological
  • Neoplasm Proteins / metabolism*
  • Oxidation-Reduction
  • Saccharomyces cerevisiae / metabolism

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Amino Acids
  • Antioxidants
  • Carrier Proteins
  • Chalcones
  • Fungal Proteins
  • Neoplasm Proteins
  • Adenosine Triphosphate
  • Glutathione
  • dihydrochalcone