Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier - PubMed (original) (raw)

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

J Wijnholds et al. J Clin Invest. 2000 Feb.

Abstract

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.

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Figures

Figure 1

Figure 1

Loss of body weight in mice lacking Mrp1 on a genetic background lacking Mdr1a Pgp and Mdr1b Pgp (TKO mice). DKO mice, TKO mice, and Mrp1–/– mice received a single intravenous dose of 60 mg/kg Etopophos®, and the loss of body weight (%) was measured over 7 days. *P < 0.001.

Figure 2

Figure 2

Mrp1 staining of frozen sections of wild-type and Mrp1-deficient tissues using monoclonal antibody MRPr1. Sections were counterstained with hematoxylin. Wild-type (a, c, e, g) and Mrp1-deficient mice (b, d, f, h). (a and b) Sections of the CP showing Mrp1 staining in the CP epithelium (a). (c and d) Sections of the salivary gland. (e and f) Sections of the oviduct. (g and h) Sections of the uterus. Bar in a represents 100 μm and applies to a–d, g and h. Bar in e represents 200 μm and applies to e and f.

Figure 3

Figure 3

Increased accumulation of etoposide into the CSF of mice lacking Mrp1 (TKO mice) compared with mice containing Mrp1 (DKO mice). Brain vesicles were cannulated and then perfused with artificial CSF. Etopophos® (60 mg/kg) was administered via a tail vein; CSF was collected for 1 hour after drug administration, and the etoposide concentration was determined. (a) The TKO mice (n = 5) accumulated 10-fold more etoposide in the CSF than did the DKO mice (n = 4) (8.1 ± 0.9 μM and 0.8 ± 0.3 μM, respectively; P < 0.001), whereas levels in total brain (3.9 ± 0.7 μmol/kg [n = 5] and 2.9 ± 0.7 μmol/kg [n = 4], TKO and DKO mice, respectively) did not differ significantly 1 hour after drug administration. (b) Etoposide levels in plasma (98 ± 12 μM [n = 5] and 114 ± 24 μM [n = 4], TKO and DKO mice, respectively) did not differ significantly 1 hour after drug administration.

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