Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier

Citation
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
Citations number
52
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
00219738 → ACNP
Volume
105
Issue
3
Year of publication
2000
Pages
279 - 285
Database
ISI
SICI code
0021-9738(200002)105:3<279:MRP1PT>2.0.ZU;2-7
Abstract
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.