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Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein

Nature Medicine volume 3, pages 1275–1279 (1997)Cite this article

Abstract

The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes1–5. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp−/−, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C4 (LTC4) from leukotriene-synthesizing cells. Moreover, the mrp−/− mice are hypersensitive to the anticancer drug etoposide. The phenbtype of mrp−/− mice is consistent with a role for MRP as the main LTC4-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous6 GS-X pump7,8 is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.

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Authors and Affiliations

  1. Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Jan Wijnholds, Raymond Evers, Manuel R. van Leusden, Carla A.A.M. Mol, Guido J.R. Zaman, Ulrich Mayer & Piet Borst

  2. Department of Pharmacy, Slotervaart Hospital, Louwesweg6, 1066 EC, Amsterdam, The Netherlands

    Jos H. Beijnen

  3. Division of Molecular Genetics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Martin Van Der Valk & Paul Krimpenfort

  4. Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Manuel R. van Leusden

  5. Department of Biotechnology and Biochemistry, Organon, Postbox 20, 5340 BH, Oss, The Netherlands

    Guido J.R. Zaman

  6. Division of Oncology and Hematology, University-Clinic Eppendorf, Martinistrasse 52, D 20246, Hamburg, Germany

    Ulrich Mayer

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Wijnholds, J., Evers, R., van Leusden, M. et al. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 3, 1275–1279 (1997). https://doi.org/10.1038/nm1197-1275

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