Mrp4 confers resistance to topotecan and protects the brain from chemotherapy.
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.
Leggas
Markos
M
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.
Adachi
Masashi
M
Scheffer
George L
GL
Sun
Daxi
D
Wielinga
Peter
P
Du
Guoqing
G
Mercer
Kelly E
KE
Zhuang
Yanli
Y
Panetta
John C
JC
Johnston
Brad
B
Scheper
Rik J
RJ
Stewart
Clinton F
CF
Schuetz
John D
JD
D000818:Animals; D000970:Antineoplastic Agents / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002560:Cerebrovascular Circulation; D002831:Choroid Plexus / Q000166:cytology / Q000378:metabolism; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019772:Topotecan / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019772:Topotecan; C073492:ABCC4 protein, human; C489540:Abcc4 protein, mouse; C489542:Abcc4 protein, rat