Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier.
Multidrug resistance protein 1 (MRP1) is a transporter protein that helps to protect normal cells and tumor cells against the influx of certain xenobiotics. We previously showed that Mrp1 protects against cytotoxic drugs at the testis-blood barrier, the oral epithelium, and the kidney urinary collecting duct tubules. Here, we generated Mrp1/Mdr1a/Mdr1b triple-knockout (TKO) mice, and used them together with Mdr1a/Mdr1b double-knockout (DKO) mice to study the contribution of Mrp1 to the tissue distribution and pharmacokinetics of etoposide. We observed increased toxicity in the TKO mice, which accumulated etoposide in brown adipose tissue, colon, salivary gland, heart, and the female urogenital system. Immunohistochemical staining revealed the presence of Mrp1 in the oviduct, uterus, salivary gland, and choroid plexus (CP) epithelium. To explore the transport function of Mrp1 in the CP epithelium, we used TKO and DKO mice cannulated for cerebrospinal fluid (CSF). We show here that the lack of Mrp1 protein causes etoposide levels to increase about 10-fold in the CSF after intravenous administration of the drug. Our results indicate that Mrp1 helps to limit tissue distribution of certain drugs and contributes to the blood-CSF drug-permeability barrier.
Wijnholds
J
J
Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
deLange
E C
EC
Scheffer
G L
GL
van den Berg
D J
DJ
Mol
C A
CA
van der Valk
M
M
Schinkel
A H
AH
Scheper
R J
RJ
Breimer
D D
DD
Borst
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000235:genetics*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005047:Etoposide / Q000493:pharmacokinetics*; D005260:Female; D019450:Genes, MDR; D051379:Mice; D018345:Mice, Knockout
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005047:Etoposide