title: Regulation of ABC transporters blood-brain barrier: the good, the bad, and the ugly.
abstract: The brain capillary endothelial cells that constitute the blood-brain barrier express multiple ABC transport proteins on the luminal, blood-facing, plasma membrane. These transporters function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites. High expression of these ABC transporters at the barrier is a major obstacle to the delivery of therapeutics, including chemotherapeutics, to the CNS. Here, I review the signals that alter ABC transporter expression and transport function with an emphasis on P-glycoprotein, Mrp2, and breast cancer resistance protein (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced (potentially bad and ugly). In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways that involve events in and on the brain capillary endothelial cells. Targeting these signaling events provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are substrates for the transporters (potentially good). The clinical usefulness of targeting signaling to reduce efflux transporter activity and improve drug delivery to the CNS remains to be established.
authors: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, North Carolina, USA. Electronic address: miller@niehs.nih.gov.
authors: David S
authors: DS
authors: Miller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human
keywords: Breast cancer related protein; Multidrug resistance-associated proteins; P-glycoprotein; Transporter activity; Transporter expression