Enhancement of glucuronosyl etoposide transport by glutathione in multidrug resistance-associated protein-overexpressing cells

Cancer Lett. 1999 Jan 8;135(1):113-9. doi: 10.1016/s0304-3835(98)00285-7.


Multidrug resistance-associated protein (MRP) has been shown to transport glutathione (GSH) S-conjugates such as leukotriene C4 (LTC4) and S-(2,4-dinitrophenyl)-glutathione (DNP-SG). On the other hand, it has while it has been reported that MRP-overexpressing cells exhibit decreased sensitivity to drugs which do not form GSH S-conjugates. In this study, we found that GSH affects the transport of glucuronosyl etoposide as a major metabolite of etoposide in MRP-overexpressing KB/VP-4 cells. The relative resistance level of KB/VP-4 cells to etoposide was 70-fold that of wild-type KB cells. Membrane vesicles prepared from KB/VP-4 cells exhibited markedly enhanced ATP-dependent transport of glucuronosyl etoposide as well as LTC4. Transport of glucuronosyl etoposide was augmented in the presence of GSH. Treatment of KB/VP-4 cells with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, resulted in about 75% depletion of cellular GSH levels, a four-fold increase of the sensitivity to etoposide and depression of glucuronosyl etoposide efflux. These results suggest that GSH plays a role in the enhancement of MRP-mediated glucuronosyl etoposide transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / biosynthesis*
  • Biological Transport / drug effects
  • Buthionine Sulfoximine / pharmacology
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm
  • Etoposide / metabolism*
  • Glucuronates / metabolism*
  • Glutathione / metabolism
  • Glutathione / pharmacology*
  • Humans
  • KB Cells
  • Leukotriene C4 / metabolism
  • Multidrug Resistance-Associated Proteins


  • ATP-Binding Cassette Transporters
  • Glucuronates
  • Multidrug Resistance-Associated Proteins
  • Leukotriene C4
  • Buthionine Sulfoximine
  • Etoposide
  • Glutathione