J. Wijnholds et al., Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier, J CLIN INV, 105(3), 2000, pp. 279-285
Multidrug resistance protein 1 (MRP1) is a transporter protein that helps t
o protect normal cells and tumor cells against the influx of certain xenobi
otics. We previously showed that Mrp1 protects against cytotoxic drugs at t
he testis-blood barrier, the oral epithelium, and the kidney urinary collec
ting 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 Mrp 1 to the tissue distribution and pharmacok
inetics of etoposide. We observed increased toxicity in the TKO mice, which
accumulated etoposide in brown adipose tissue, colon, salivary gland, hear
t, and the female urogenital system. Immunohistochemical staining revealed
the presence of Mrp 1 in the oviduct, uterus, salivary gland, and choroid p
lexus (CP) epithelium. To explore the transport function of Mrp 1 in the CP
epithelium, we used TKO and DKO mice cannulated for cerebrospinal fluid (C
SF). We show here that the lack of Mrp 1 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.