DescriptionThe blood-brain barrier (BBB) restricts the exchange of numerous endo- and xenobiotics between the circulation and the brain parenchyma. The primary cellular component of the BBB is the brain microvascular endothelium which possess multiple mechanisms of protection, one of which is the presence of the transporters. Multidrug resistance protein 1 (MDR1, ABCB1, P-glycoprotein) and breast cancer resistance protein (BCRP, ABCG2) are key efflux transporters located along the apical surface of BBB endothelial cells. Both transporters play significant roles in extruding chemicals from the brain endothelium back to the circulation. Prior studies in cancer cells have demonstrated that pharmacological inhibition of histone deacetylases (HDACs) can up-regulate the expression and function of MDR1 and BCRP transporters due to enhanced histone acetylation. The purpose of this dissertation was to determine the extent to which inhibition of HDAC enzymes regulates efflux transporters at the BBB. In immortalized human brain capillary endothelial (hCMEC/D3) cells, a human model of the BBB, both mRNA and protein expression of MDR1 and BCRP were up-regulated by multiple HDAC inhibitors including valproic acid (VPA), apicidin, and suberoylanilide hydroxamic acid (SAHA). Increased MDR1 expression corresponded with enhanced MDR1 function, as indicated by reduced intracellular accumulation of rhodamine 123, a fluorescent substrate of MDR1. Further investigation of the molecular mechanisms underlying transporter up-regulation in hCMEC/D3 cells revealed that SAHA increased the binding of acetylated histone H3K9/14 proteins within the MDR1 promoter region containing response elements for the aryl hydrocarbon receptor (AHR). Pharmacological manipulation was used to assess the role of AHR as a transcriptional activator of MDR1 following HDAC inhibition. Concurrent treatment with beta-naphthoflavone, an AHR activator, amplified SAHA-mediated induction of MDR1 expression while CH-223191, an AHR inhibitor, prevented the induction of MDR1 by SAHA. Moreover, binding of AHR was increased at the MDR1 promoter in SAHA-treated hCMEC/D3 cells. These data indicate that histone acetylation and AHR signaling cooperatively regulate MDR1 expression following pharmacological inhibition of HDACs. Finally, a 7-day in vivo study demonstrated that HDAC inhibitors can regulate Mdr1 and Bcrp transporter expression in the brains of mice in a region-specific manner. Collectively, the data presented in this dissertation identify a novel epigenetic mechanism that can regulate the MDR1 and BCRP transporters at the BBB and potentially affect levels of neuroactive compounds in the brain.