Elsevier

Advanced Drug Delivery Reviews

Volume 56, Issue 12, 14 October 2004, Pages 1741-1763
Advanced Drug Delivery Reviews

Review
Efflux transport systems for organic anions and cations at the blood–CSF barrier

https://doi.org/10.1016/j.addr.2004.07.007Get rights and content

Abstract

The choroid plexus (CP), located in the lateral, third and fourth ventricles, is the site of elimination of xenobiotics and endogenous waste from the cerebrospinal fluid (CSF) together with convective flow associated with CSF turnover. Active efflux transport systems, as well as metabolic enzymes in the choroid plexus epithelial cells (CPE), which form a tight monolayer, play a protective role by facilitating the elimination of xenobiotics including drugs and endogenous waste from the CSF to prevent their accumulation in the central nervous system. Except in the case of lipophilic cationic and neutral compounds, uptake and efflux transporters carry out the vectorial transport across the cell monolayer to transfer their common substrates efficiently from the CSF to the blood side. Many published studies have given us some insights into the uptake mechanisms for organic compounds at the brush border side of the CP. Organic anion transporters, such as Oatp3 and Oat3, play a major role in the uptake of amphipathic and hydrophilic organic anions, respectively, at the brush border surface of the CPE, while the organic cation transporters, Oct2 and/or Oct3, have been suggested to be involved in the uptake of hydrophilic organic cations. In contrast, the molecular characteristics of basolateral transporters have not been fully elucidated. Mrp1 is involved in the excretion of etoposide at the basolateral membrane of the CPE, but its contribution to the excretion of organic anions, especially amphipathic conjugated metabolites, remains controversial. The present manuscript summarizes the efflux transport mechanisms at the choroid plexus and focuses on the molecular characteristics of these transporters.

Introduction

The choroid plexus (CP) is a leaf-like, highly vascularized organ that protrudes into the ventricles. It secretes the cerebrospinal fluid (CSF) which fills the ventricular system and the subarachnoideal space, and circulates around the brain and spinal cord before it is reabsorbed into the blood circulation primarily by the arachnoid villi [1], [2]. The CSF maintains the working environment of the brain by providing buoyancy to protect the brain and by acting as a buffer reservoir or as a source of necessary osmolytes. The CP consists of fenestrated capillaries surrounded by a tight monolayer of epithelial cells. The choroid plexus epithelial cells (CPE) are polarized to form brush border (BBM) and basolateral (BLM) membranes facing towards the CSF and plasma, respectively. Due to fenestrated capillaries in the CP, compounds in the blood have free access to the BLM of the CPE; however, tightly sealed cell junctions between the epithelial cells prevent free exchange of compounds between the blood and CSF, and provide a barrier function between the CSF and the blood circulation (blood–CSF barrier). In addition, the CPE has detoxification systems, including metabolic enzymes and efflux transport systems, to facilitate the elimination of xenobiotics and endogenous wastes from the CSF to the circulating blood. This, together with the blood–brain brain barrier formed by brain capillary endothelial cells, prevents their accumulation in the central nervous system [3], [4], [5], [6], [7], [8]. Drugs acting in the central nervous system have to overcome these barriers to achieve clinically significant concentrations in the central nervous system.

The efflux transport of organic compounds across the cell monolayer is characterized by vectorial transport, which plays a major role in the hepatobiliary transport and urinary secretion of organic anions and hydrophilic organic cations. Recently, a number of transporters have been cloned and their functional characterization has been carried out [6], [9], [10], [11], [12], [13], [14], [15]. This has allowed the elucidation of the molecular characteristics of the efflux transport systems expressed at the CP as summarized in Table 1. The primary purpose of the present manuscript is to illustrate the efflux transport systems for organic anions and cations in the CP.

Section snippets

Pharmacokinetic quantification of efflux transport from the CSF

A sequential determination of the CSF concentration after intracerebroventricular (i.c.v.) administration (CCSF) allows us to determine the elimination rate constant (ke) as described by the following differential equation,dCCSFdt=ke·CCSF=CLCSF/Vd,CSF·CCSFwhere CLCSF represents the elimination clearance from the CSF. The time profile of the drug concentration in the CSF is affected not only by the elimination clearance, but also by the distribution volume in the ventricles (Vd,CSF). The CLCSF

Molecular characteristics of drug transporters

In this section, the molecular characteristics of the uptake transporters, such as Oatp/OATP, Oat/OAT, Oct/OCT and PEPT are described, as well as the ABC transporters, such as Mrp/MRP and P-glycoprotein. The prefixes m, r and h represent different species, i.e. mice, rats and humans, in the following text.

Efflux transport mechanisms for organic anions in the choroid plexus

The uptake mechanisms for organic anions at the brush border surface of the CP can be subdivided into two groups in terms of substrate specificity: One for amphipathic organic anions, such as taurocholate, E217βG and estrone sulfate, and the other for hydrophilic and small organic anions, such as PAH and benzylpenicillin (Fig. 1). These two systems have similar characteristics to the hepatobiliary and urinary transport systems for organic anions, respectively, and are primarily accounted for by

Efflux transport mechanism for organic cations in the choroid plexus

Miller and Ross [144] measured the extraction of NMN in vivo using the ventriculocisternal perfusion technique. The extraction of NMN during perfusion from the lateral ventricles to the cisternal magna was greater than that of inulin and was reduced by the addition of mepiperhenidol to the perfusate, suggesting involvement of an organic cation transporter in the extraction [144]. Other organic cations, such as cimetidine, choline, and TEA, typical substrates of renal organic cation

Discussion and future aspects

The present review summarizes the current status of the efflux transport mechanisms for organic ions in the CP. The many published studies have provided molecular insights into the uptake systems operating at the BBM of the CP. Due to limitations in methodology, the excretion process for organic ions has not been fully characterized yet and the molecular characteristics of the transporters involved in this process remain unknown. ABC transporters, such as MRPs and/or alternatively membrane

References (154)

  • G.A. Kullak-Ublick et al.

    Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver

    Gastroenterology

    (1995)
  • G.A. Kullak-Ublick et al.

    Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain

    FEBS Lett.

    (1998)
  • T. Nishio et al.

    Molecular identification of a rat novel organic anion transporter moat1, which transports prostaglandin D(2), leukotriene C(4), and taurocholate

    Biochem. Biophys. Res. Commun.

    (2000)
  • I. Tamai et al.

    Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family

    Biochem. Biophys. Res. Commun.

    (2000)
  • G.A. Kullak-Ublick et al.

    Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver

    Gastroenterology

    (2001)
  • K. Sato et al.

    Expression of organic anion transporting polypeptide E (OATP-E) in human placenta

    Placenta

    (2003)
  • A. Enomoto et al.

    Molecular identification of a novel carnitine transporter specific to human testis. Insights into the mechanism of carnitine recognition

    J. Biol. Chem.

    (2002)
  • D.H. Sweet et al.

    Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice

    J. Biol. Chem.

    (2002)
  • M. Alebouyeh et al.

    Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites

    J. Pharmacol. Sci.

    (2003)
  • H. Kusuhara et al.

    Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain

    J. Biol. Chem.

    (1999)
  • T. Deguchi et al.

    Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney

    Kidney Int.

    (2002)
  • T. Sekine et al.

    Expression cloning and characterization of a novel multispecific organic anion transporter

    J. Biol. Chem.

    (1997)
  • D.H. Sweet et al.

    Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney

    J. Biol. Chem.

    (1997)
  • T. Sekine et al.

    Identification of multispecific organic anion transporter 2 expressed predominantly in the liver

    FEBS Lett.

    (1998)
  • D.H. Sweet et al.

    Ventricular choline transport: a role for organic cation transporter 2 expressed in choroid plexus

    J. Biol. Chem.

    (2001)
  • M. Okuda et al.

    cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2

    Biochem. Biophys. Res. Commun.

    (1996)
  • R. Kekuda et al.

    Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta

    J. Biol. Chem.

    (1998)
  • X. Wu et al.

    Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain

    J. Biol. Chem.

    (1998)
  • I. Tamai et al.

    Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2

    J. Biol. Chem.

    (1998)
  • T. Sekine et al.

    Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine

    Biochem. Biophys. Res. Commun.

    (1998)
  • I. Tamai et al.

    Molecular and functional characterization of organic cation/carnitine transporter family in mice

    J. Biol. Chem.

    (2000)
  • M.E. Ganapathy et al.

    Interaction of anionic cephalosporins with the intestinal and renal peptide transporters PEPT1 and PEPT2

    Biochim. Biophys. Acta

    (1997)
  • M.E. Ganapathy et al.

    Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2

    Biochem. Biophys. Res. Commun.

    (1998)
  • H. Shen et al.

    Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in choroid plexus

    J. Biol. Chem.

    (2003)
  • H.H. Kao et al.

    cDNA cloning and genomic organization of the murine MRP7, a new ATP-binding cassette transporter

    Gene

    (2002)
  • E. Hopper et al.

    Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily

    Cancer Lett.

    (2001)
  • T. Speake et al.

    Mechanisms of CSF secretion by the choroid plexus

    Microsc. Res. Tech.

    (2001)
  • M.B. Segal

    The choroid plexuses and the barriers between the blood and the cerebrospinal fluid

    Cell. Mol. Neurobiol.

    (2000)
  • B. Gao et al.

    Organic anion transport across the choroid plexus

    Microsc. Res. Tech.

    (2001)
  • N. Strazielle et al.

    Demonstration of a coupled metabolism–efflux process at the choroid plexus as a mechanism of brain protection toward xenobiotics

    J. Neurosci.

    (1999)
  • R. Spector

    Drug transport in the mammalian central nervous system: multiple complex systems

    Pharmacology

    (2000)
  • N. Mizuno et al.

    Impact of drug transporter studies on drug discovery and development

    Pharmacol. Rev.

    (2003)
  • J.F. Ghersi-Egea et al.

    Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus

    Microsc. Res. Tech.

    (2001)
  • F.G. Russel et al.

    Molecular aspects of renal anionic drug transport

    Annu. Rev. Physiol.

    (2002)
  • H. Koepsell et al.

    Molecular pharmacology of organic cation transporters in kidney

    J. Membr. Biol.

    (1999)
  • G. Burckhardt et al.

    Molecular characterization of the renal organic anion transporter 1

    Cell Biochem. Biophys.

    (2002)
  • H. Suzuki et al.

    Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2

    Semin. Liver Dis.

    (1998)
  • J.M. Collins et al.

    Distributed model for drug delivery to CSF and brain tissue

    Am. J. Physiol.

    (1983)
  • H. Dai et al.

    Drug transport studies using quantitative microdialysis

    Methods Mol. Med.

    (2003)
  • H. Kusuhara et al.

    Brain efflux index method. Characterization of efflux transport across the blood–brain barrier

    Methods Mol. Med.

    (2003)
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