Doxorubicin- and daunorubicin-glutathione conjugates, but not unconjugated drugs, competitively inhibit leukotriene C4 transport mediated by MRP/GS-X pump

Waldemar Priebe, Marta Krawczyk, M. Tien Kuo, Yoshiaki Yamane, Niramol Savaraj, Toshihisa Ishikawa

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Overexpression of the multidrug resistance-associated protein (MRP1) gene encoding a human GS-X pump in cultured cells resulted in increased cellular resistance to antitumor agents, including doxorubicin (Dox) and daunomycin (Dau), as well as certain heavy metals. However, studies with membrane vesicles prepared from the resistant cells revealed that Dox and Dau are poor substrates for the transport mediated by MRP/GS-X pump, suggesting that metabolic modifications of these drugs might be required for the transport. To test this hypothesis, we prepared four glutathione conjugates by linking the cysteine residue of GSH to Dox and Dau at either the C-7 or C-14 position. The affinity of the synthesized conjugates toward MRP/GS-X pump was examined in the LTC4 transport assay using membrane vesicles prepared from an MRP1 gene-overexpressing cell line, SR3A. Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 μM GS-Dox or GS-Dau conjugates completely inhibited the transport. Kinetic analyses revealed that the inhibition by these GS-conjugates is competitive with Ki values ranging from 60 to 200 nM, suggesting that these compounds have high affinities toward MRP/GS-X pump and share the common binding site(s) with LTC4. Our present results support the hypothesis that glutathionation can facilitate the transport of anthracyclines by the MRP/GS-X pump.

Original languageEnglish (US)
Pages (from-to)859-863
Number of pages5
JournalBiochemical and biophysical research communications
Volume247
Issue number3
DOIs
StatePublished - Jun 29 1998

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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