Research ArticlesDo Multidrug Resistance‐Associated Protein‐1 and ‐2 Play Any Role in the Elimination of Estradiol‐17β‐Glucuronide and 2,4‐Dinitrophenyl‐S‐Glutathione Across the Blood–Cerebrospinal Fluid Barrier?
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INTRODUCTION
The choroid plexus (CP), which forms the blood–cerebrospinal fluid barrier (BCSFB), secretes cerebrospinal fluid (CSF) and regulates its composition by active and selective transport processes.1 Within the CP, the complex vascular bed is composed of some fenestrated but permeable capillaries that permit all molecules smaller than proteins to gain easy access to the basolateral membrane of the choroid epithelial cells. For this reason, the anatomical entity of the BCSFB consists of choroid
Chemicals
[3H]Estradiol‐17β‐glucuronide (E217βG; 40.5 Ci/mmol), [14C]mannitol (51 mCi/mmol), and [14C]urea (40 mCi/mmol) were purchased from PerkinElmer Life Sciences (Boston, MA). [3H]2,4‐Dinitrophenyl‐S‐glutathione (DNP‐SG) was synthesized enzymatically using [3H]glutathione (PerkinElmer Life Science), 1‐chloro‐2,4‐dinitrobenzene, and glutathione S‐transferase (Sigma Chemical, St. Louis, MO) as described previously, and the purity (>90%) was checked by high‐performance liquid chromatography (HPLC).19
Elimination of E217βG and DNP‐SG from the CSF after Intracerebroventricular Administration in Mice
CSF concentrations of E217βG and DNP‐SG after intracerebroventricular administration in wild‐type and Mrp1 knockout mice are shown in Figure 1 as remaining concentration ratios of E217βG and DNP‐S, normalized by the simultaneously administered mannitol. The elimination of E217βG and DNP‐SG from CSF after intracerebroventricular administration was much faster than that of mannitol, the elimination of which is mediated entirely by simple diffusion and CSF turnover,21 both in wild‐type and Mrp1
DISCUSSION
E217βG is rapidly removed from the CSF by an efficient efflux transport system at the CP. Although Oatp3 accounts for the uptake of E217βG by isolated rat CP, the transporter responsible for the basolateral excretion remains to be identified. The present study highlighted Mrp1 and Mrp2 as candidate transporters responsible for the basolateral excretion of amphiphatic organic anions.
E217βG, a typical Mrp1 substrate, was eliminated from the CSF in both Mrp1 knockout and wild type mice after
Acknowledgements
This work was supported by the research grant from the Japan Foundation For Aging and Health.
REFERENCES (33)
- et al.
Role of efflux transport across the blood‐brain barrier and blood‐cerebrospinal fluid barrier on the disposition of xenobiotics in the central nervous system
Adv Drug Deliv Rev
(1997) - et al.
Efflux transport systems for drugs at the blood‐brain barrier and blood‐cerebrospinal fluid barrier (Part 1)
Drug Discov Today
(2001) - et al.
Structural, mechanistic and clinical aspects of MRP1
Biochim Biophys Acta
(1999) - et al.
The (patho)physiological functions of the MRP family
Drug Resist Update
(2000) - et al.
Transport of thyroxine across the blood‐brain barrier is directed primarily from brain to blood in the mouse
Life Sci
(1985) - et al.
Conjugate export pumps of the multidrug resistance protein (MRP) family: Localization, substrate specificity, and MRP2‐mediated drug resistance
Biochim Biophys Acta
(1999) - et al.
Transport of cyclic nucleotides and estradiol 17‐beta‐D‐glucuronide by multidrug resistance protein 4. Resistance to 6‐mercaptopurine and 6‐thioguanine
J Biol Chem
(2001) - et al.
The multidrug resistance protein 5 functions as an ATP‐dependent export pump for cyclic nucleotides
J Biol Chem
(2000) Transport of nutrients across the choroid plexus
Microscop Res Technol
(2001)- et al.
Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance‐associated protein contribute to the blood‐cerebrospinal‐fluid drug‐permeability barrier
Proc Natl Acad Sci USA
(1999)