Brain region-specific regulation of histone acetylation and efflux transporters in mice

J Biochem Mol Toxicol. 2019 Jun;33(6):e22318. doi: 10.1002/jbt.22318. Epub 2019 Mar 21.


Multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) protect the brain by restricting the passage of chemicals across the blood-brain barrier. Prior studies have demonstrated the epigenetic regulation of MDR1 and BCRP in cancer cells treated with histone deacetylase (HDAC) inhibitors that enhance histone acetylation and gene transcription. In the present study, we tested the in vivo effects of two HDAC inhibitors, valproic acid (VPA; 400 mg/kg) and apicidin (5 mg/kg), on Mdr1 and Bcrp transporter expression in brain regions of adult male mice injected intraperitoneally daily for 7 days. VPA increased Mdr1 protein expression in the striatum (70%) and Bcrp protein in the midbrain (30%). Apicidin enhanced striatal Mdr1 protein (30%) and hippocampal Bcrp protein (20%). Transporter induction correlated with increased histone H3 acetylation in discrete brain regions. In conclusion, HDAC inhibitors upregulate transporter proteins in vivo, which may be important in regulating regional xenobiotic disposition within the brain.

Keywords: Abcb1; Abcg2; P-glycoprotein; brain; breast cancer resistance protein (BCRP); histone deacetylase (HDAC) inhibitor; multidrug resistance protein 1 (MDR1); transporter.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / biosynthesis*
  • Acetylation / drug effects
  • Animals
  • Brain / metabolism*
  • Gene Expression Regulation / drug effects*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Histones / metabolism*
  • Male
  • Mice
  • Peptides, Cyclic / pharmacology*
  • Valproic Acid / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Abcg2 protein, mouse
  • Histone Deacetylase Inhibitors
  • Histones
  • Peptides, Cyclic
  • apicidin
  • Valproic Acid
  • Histone Deacetylases