Elsevier

Vascular Pharmacology

Volume 38, Issue 6, June 2002, Pages 339-348
Vascular Pharmacology

Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier

https://doi.org/10.1016/S1537-1891(02)00201-XGet rights and content

Abstract

1. The blood–brain barrier (BBB) contributes to brain homeostastis and fulfills a protective function by controlling the access of solutes and toxic substances to the central nervous system (CNS). The efflux transporter P-glycoprotein (P-gp) is a key element of the molecular machinery that confers special permeability properties to the BBB. 2. P-gp, which was initially recognized for its ability to expel anticancer drugs from multidrug-resistant cancer cells, is strongly expressed in brain capillaries. Its expression in the BBB limits the accumulation of many hydrophobic molecules and potentially toxic substances in the brain. 3. The purpose of this review is to summarize the current state of knowledge about the expression of P-gp, its cellular localization as well as its possible functions in the BBB.

Section snippets

Introduction: The blood–brain barrier (BBB) and P-glycoprotein (P-gp)

The brain is shielded against potentially toxic substances by the presence of two barrier systems: the BBB and the blood–cerebrospinal fluid barrier (BCSFB). Because its surface area is approximately 5000-fold greater than that of the BCSFB, the BBB is considered to be the major route for the uptake of endogenous and exogenous ligands into the brain parenchyma Pardridge, 1999, Kusuhara and Sugiyama, 2001. The BBB is formed by brain capillary endothelial cells (BCECs), which are closely sealed

The efflux transporter P-gp

P-gp is a membrane transporter of the ABC (ATP binding cassette) superfamily that was initially described in the field of cancer research Biedler and Riehm, 1970, Ling and Thompson, 1974. Its expression was associated with inherent or acquired multidrug resistance (MDR) phenotype by cancer cells Biedler and Riehm, 1970, Dano, 1973. This phenotype renders the cells resistant not only to the agent to which they are exposed but also to other agents of unrelated structure or function. By actively

P-gp substrates and reversal agents

The first molecules identified as P-gp substrates were generally from natural sources, either plants or microorganisms. Their structures often included hydrophobic regions, planar aromatic domains in particular, as well as tertiary amino groups or positive charges at physiological pH (Seelig and Landwojtowicz, 2000). Among the transported anticancer agents are vinca alkaloids, epipodophyllotoxins, anthracyclines, taxanes and antibiotics such as erythromycin and tetracycline Gottesman and

Localization of P-gp

The expression of P-gp in human tissues has been the object of numerous investigations utilizing various experimental approaches such as in situ hybridisation and immunocytochemistry Fojo et al., 1987, Thiebaut et al., 1987, Cordon-Cardo et al., 1990. MDR1 P-gp is present in many human tissues such as liver, kidney, intestines and adrenal glands as well as in blood–tissue barriers including the placenta, testis capillaries and brain capillaries Cordon-Cardo et al., 1989, Jetté et al., 1993. We

P-gp in brain tumors

Clinical progress in the treatment of brain tumors has been slow and one of the problems impeding treatment of these tumors is their weak response to anticancer drugs. The effectiveness of chemotherapy and immunotherapy in the CNS is often impaired by the BBB, which physically restricts the entry of large and/or hydrophilic drugs into the brain. The low response to chemotherapy may also depend on tumor blood flow, the integrity of the blood–tumor barrier and inherent or acquired MDR phenotype

Role of P-gp in brain capillaries

In brain capillaries, P-gp appears to play an important role in preventing many hydrophobic molecules from crossing the BBB and reaching the CNS. However, the exact physiological function of P-gp in the BBB is not completely understood. A growing body of evidence links P-gp to physiological roles distinct from its initially recognized function as a drug efflux system (Fig. 3).

Other MDR transporters in brain capillaries

It has been reported that efflux transporters other than P-gp are also expressed in brain capillaries. For instance, members of the multidrug resistance-associated protein (MRP) family have been detected at the BBB site. In humans, nine MRP homologues have been identified Borst et al., 2000b, Bera et al., 2001, Bera et al., 2002. All the members of the MRP family are distributed throughout most human tissues (Flens et al., 1996). MRP1, which was first described by Cole et al. (1992), was

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