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Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug

J Wijnholds1, R Evers, M R van Leusden

  • 1Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam.

Nature Medicine
|November 14, 1997
PubMed

Insights

Mice lacking the multidrug resistance-associated protein (MRP) show impaired inflammatory responses due to reduced leukotriene C4 secretion and increased sensitivity to etoposide, suggesting MRP

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • The multidrug resistance-associated protein (MRP) is involved in cellular efflux of drugs, xenobiotics, and leukotrienes.
  • Elevated MRP levels in cancer cells contribute to multidrug resistance (MDR) by reducing intracellular drug accumulation.
  • The precise physiological functions of MRP remain incompletely understood.

Purpose of the Study:

  • To elucidate the physiological roles of MRP by generating and characterizing MRP-deficient mice.
  • To investigate the impact of MRP deficiency on inflammatory responses and drug sensitivity.

Main Methods:

  • Generation of MRP-deficient mice (mrp-/-) using embryonic stem cell technology.
  • Assessment of inflammatory response and leukotriene C4 secretion in mrp-/- mice.
  • Evaluation of etoposide sensitivity in mrp-/- mice.

Main Results:

  • MRP-deficient mice are viable and fertile but exhibit an impaired response to inflammatory stimuli.
  • This impairment is linked to decreased secretion of leukotriene C4 from relevant cells.
  • MRP-deficient mice display hypersensitivity to the anticancer drug etoposide.

Conclusions:

  • MRP functions as a critical exporter of leukotriene C4 in inflammatory pathways.
  • MRP plays a significant role in cellular drug efflux, particularly in drug-sensitive cells.
  • The dispensability of MRP in mice suggests potential therapeutic strategies targeting MDR using MRP-specific agents.

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