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Multidrug resistance protein 4 protects bone marrow, thymus, spleen, and intestine from nucleotide analogue-induced

Martin G Belinsky1, Ping Guo, Kun Lee

  • 1Medical Science Division, Department of Pathology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

Cancer Research
|January 11, 2007
PubMed

Insights

Multidrug resistance protein 4 (Mrp4) acts as a resistance factor for nucleoside analogues in vivo. Mrp4-null mice show increased toxicity and lethality, indicating Mrp4

Area of Science:

  • Pharmacology and Molecular Biology
  • Drug Transport and Resistance Mechanisms

Background:

  • Nucleoside analogues are crucial therapeutics for cancer, viral, and inflammatory diseases.
  • ATP-binding cassette transporters, like multidrug resistance protein 4 (Mrp4), can efflux these analogues.
  • The in vivo role of Mrp4 in nucleoside analogue pharmacologic function remains largely uncharacterized.

Purpose of the Study:

  • To investigate the in vivo function of Mrp4 as an endogenous resistance factor.
  • To determine the impact of Mrp4 deficiency on the pharmacologic effects of nucleoside analogues.

Main Methods:

  • Utilized Mrp4-null (Mrp4-/-) mice as a model system.
  • Employed the nucleotide analogue 9'-(2'-phosphonylmethoxyethyl)-adenine (PMEA) as a probe.
  • Assessed PMEA levels, lethality, tissue toxicity, and brain penetration in Mrp4-/- mice.

Main Results:

  • Mrp4-null mice exhibited increased lethality and significant toxicity in bone marrow, spleen, thymus, and gastrointestinal tract upon PMEA treatment.
  • Plasma PMEA levels were not altered in Mrp4-null mice.
  • Enhanced PMEA penetration into the brain was observed in Mrp4-null mice.

Conclusions:

  • Mrp4 functions as an endogenous resistance factor in vivo for nucleoside analogues.
  • Mrp4 deficiency leads to increased tissue sensitivity and toxicity to nucleoside analogues.
  • Mrp4 may contribute to the blood-brain barrier integrity for nucleoside-based analogues.

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