Histone Modification is a Novel Epigenetic Mechanism to Up‐Regulate Human Blood‐Brain Barrier Transporters

Abstract

Multidrug Resistance Protein 1 (MDR1, ABCB1) and the Breast Cancer Resistance Protein (BCRP, ABCG2) expressed at the blood‐brain barrier (BBB) are key efflux transporters that extrude chemicals from the BBB and regulate the efficacy and/or toxicity of chemicals in the brain. Prior studies in cancer cells have pointed to the ability of histone deacetylase (HDAC) inhibitors to modulate the expression and function of MDR1 and BCRP. However, whether or not such regulation occurs at the BBB is not known. Here we sought to test whether HDAC inhibitors could potentially alter expression and function of MDR1 and BCRP at the BBB. To test this, we treated immortalized human brain capillary endothelial (hCMEC/D3) cells, a model of the BBB, with six different HDAC inhibitors, valproic acid (VPA), sodium butyrate (NaB), romidepsin, apicidin, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), and assessed for expression and function of MDR1 and BCRP. HDAC inhibition following treatment was confirmed by increased levels of acetylated histone H3 protein. After 12 h of treatment, VPA, apicidin, SAHA, and TSA up‐regulated MDR1 mRNA levels between 50% and 200%. All six HDAC inhibitors significantly induced BCRP mRNA levels between 100% and 270%. Similarly, the protein expression of MDR1 and BCRP transporters was up‐regulated about two‐fold at 24 h. Enhanced MDR1 expression corresponded with reduced intracellular accumulation of the substrate rhodamine 123. Collectively, these results demonstrate that HDAC inhibitors up‐regulate MDR1 and BCRP transporters at the BBB by modifying histone acetylation. The clinical use of HDAC inhibitors may enhance efflux transporter activity at the BBB and restrict access of xenobiotics to the brain.Support or Funding InformationSupported by R01ES021800, P30ES005022.