Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier

Abstract

ATP-binding cassette (ABC) transporters are important selective elements of the blood-brain barrier. They line the luminal plasma membrane of the brain capillary endothelium, facing the vascular space, and both protect the central nervous system from entry of neurotoxicants and limit the access of therapeutic drugs to the brain parenchyma. Recent studies highlight the multiple signaling pathways through which the expression and activity of P-glycoprotein and other ABC transporters are modulated in response to xenobiotics, stress and disease. The results show that increased transporter expression occurs in response to signals that activate specific transcription factors, including pregnane-X receptor, constitutive androstane receptor, nuclear factor-kappaB and activator protein-1, and that reduced transporter activity occurs rapidly and reversibly in response to signaling through Src kinase, protein kinase C and estrogen receptors. A detailed understanding of such regulation can provide the basis for improved neuroprotection and enhanced therapeutic drug delivery to the brain.

Figure 1

Distribution of selected drug transporters at the BBB. ABC transporters are ATP-driven xenobiotic efflux pumps that can be highly polyspecific (P-glycoprotein is an extreme example), with overlapping substrate specificities that are briefly outlined for each in the boxes. There is considerable controversy over the localization of essentially all ABC transporters in brain capillaries [1, 6]. It is likely that species differences in protein expression levels and cellular transporter distribution as well as differences in detection techniques across laboratories underlie many of the conflicts that permeate the literature. Nevertheless, when expressed on the luminal plasma membrane, ABC transporters provide an active, structure-sensitive barrier to drugs within the vascular space. Other transporters shown are members of the SLC superfamily and handle primarily organic anions and weak organic acids. Substrates for these transporters include some drugs, for example NSAIDS, as well as drug metabolites and waste products of normal CNS metabolism. They, along with luminal ABC transporters, provide a two-stage system for active and efficient excretion of potentially toxic chemicals and metabolites from the CNS.

Figure 2

Signals that rapidly decrease P-glycoprotein transport activity at the BBB. Two signaling pathways (proinflammatory and vascular endothelial growth factor (VEGF) – induced) were initially described in rat brain capillaries through the use of pharmacological tools. They have been validated in vivo, in that activating each of the pathways rapidly and substantially increases brain uptake of verapamil and morphine, both P-glycoprotein substrates [25, 26, 66, 68]. Because signaling through these pathways has the potential to rapidly and transiently reduce P-glycoprotein activity without altering expression, targeting downstream steps provide a strategy for improving delivery to the brain of drugs that are P-glycoprotein substrates. Abbreviations: lipopolysaccharide (LPS), tumor necrosis factor (TNF), endothelin (ET), toll-like receptor (TLR), inducible nitric oxide synthase (iNOS), protein kinase C (PKC)