title: Activating PKC-β1 at the blood-brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS.
abstract: Upregulation of blood-brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-β1 (PKC-β1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-β1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-β1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries and reversed the effect of dioxin on brain uptake of verapamil in dioxin-dosed rats. Thus, targeting BBB PKC-β1 may be an effective strategy to improve drug delivery to the brain, even in drug-resistant individuals.
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Wang
authors.forename: Brian T
authors.initials: BT
authors.lastname: Hawkins
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology*; D004789:Enzyme Activation; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D014700:Verapamil; D011493:Protein Kinase C; D064546:Protein Kinase C beta