School of Graduate Studies, Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey.
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.
多药耐药蛋白 1（MDR1）和乳腺癌耐药蛋白（BCRP）通过限制化学物质穿过血脑屏障来保护大脑。先前的研究表明，组蛋白去乙酰化酶（HDAC）抑制剂处理的癌细胞中 MDR1 和 BCRP 的表观遗传调控增强了组蛋白乙酰化和基因转录。在本研究中，我们测试了两种 HDAC 抑制剂，丙戊酸（VPA；400mg/kg）和阿皮西林（apicidin；5mg/kg），对成年雄性小鼠腹腔注射 7 天每日一次后大脑区域中 Mdr1 和 Bcrp 转运蛋白表达的体内影响。VPA 增加了纹状体中的 Mdr1 蛋白表达（70%）和中脑的 Bcrp 蛋白（30%）。阿皮西林增强了纹状体中的 Mdr1 蛋白（30%）和海马中的 Bcrp 蛋白（20%）。转运蛋白诱导与特定脑区组蛋白 H3 乙酰化增加相关。总之，HDAC 抑制剂在体内上调转运蛋白，这可能对调节大脑内的外来物质分布很重要。
