Mrp4 confers resistance to topotecan and protects the brain from chemotherapy

Markos Leggas, Masashi Adachi, George L. Scheffer, Daxi Sun, Pieter Wielinga, Guoqing Du, Kelly E. Mercer, Yanli Zhuang, John C. Panetta, Brad Johnston, Rik J. Scheper, Clinton F. Stewart, John D. Schuetz

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The role of the multidrug resistance protein MRP4/ABCC4 in vivo remains undefined. To explore this role, we generated Mrp4-deficient mice. Unexpectedly, these mice showed enhanced accumulation of the anticancer agent topotecan in brain tissue and cerebrospinal fluid (CSF). Further studies demonstrated that topotecan was an Mrp4 substrate and that cells overexpressing Mrp4 were resistant to its cytotoxic effects. We then used new antibodies to discover that Mrp4 is unique among the anionic ATP-dependent transporters in its dual localization at the basolateral membrane of the choroid plexus epithelium and in the apical membrane of the endothelial cells of the brain capillaries. Microdialysis sampling of ventricular CSF demonstrated that localization of Mrp4 at the choroid epithelium is integral to its function in limiting drug penetration into the CSF. The topotecan resistance of cells overexpressing Mrp4 and the polarized expression of Mrp4 in the choroid plexus and brain capillary endothelial cells indicate that Mrp4 has a dual role in protecting the brain from cytotoxins and suggest that the therapeutic efficacy of central nervous system-directed drugs that are Mrp4 substrates may be improved by developing Mrp4 inhibitors.
Original languageEnglish
JournalMolecular and Cellular Biology
Volume24
Issue number17
Pages (from-to)7612-7621
ISSN0270-7306
DOIs
Publication statusPublished - 2004
Externally publishedYes

Keywords

  • Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] mouse common
  • Mrp4 expression
  • topotecan 123948-87-8 antineoplastic-drug, enzyme inhibitor-drug
  • 10060, Biochemistry studies - General
  • 12512, Pathology - Therapy
  • 14504, Cardiovascular system - Physiology and biochemistry
  • 20504, Nervous system - Physiology and biochemistry
  • 22002, Pharmacology - General
  • 24008, Neoplasms - Therapeutic agents and therapy
  • Neural Coordination
  • Transport and Circulation
  • brain capillaries circulatory system, nervous system
  • cerebrospinal fluid nervous system
  • choroid plexus nervous system
  • microdialysis laboratory techniques
  • Biochemistry and Molecular Biophysics
  • Cardiovascular System
  • Nervous System
  • Pharmacology

Cite this

Leggas, M., Adachi, M., Scheffer, G. L., Sun, D., Wielinga, P., Du, G., Mercer, K. E., Zhuang, Y., Panetta, J. C., Johnston, B., Scheper, R. J., Stewart, C. F., & Schuetz, J. D. (2004). Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Molecular and Cellular Biology, 24(17), 7612-7621. https://doi.org/10.1128/MCB.24.17.7612–7621.2004