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

Abstract

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.

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

“…Furthermore, SCFAs were shown to induce Mdr1 mRNA in livers of male Sprague-Dawley rats following intraperitoneal doses of VPA and butyrate for 7 days (Eyal et al, 2006). Likewise, 7-day intraperitoneal treatment with VPA, a brain-penetrable HDAC inhibitor, significantly up-regulated the Mdr1 protein in the striatum of C57BL/6 mice along with levels of acetylated histone H3K9/14 (You et al, 2019a). Such in vivo data extend the in vitro findings and suggest that SCFA HDAC inhibitors can alter MDR1 expression in normal healthy tissues as well as cancer cell lines.…”

“…Several studies have delved deeper to delineate the mechanisms by which HDAC inhibitors alter efflux transporter expression in various cell types. These studies have consistently revealed a correlation between transporter regulation and alterations in the acetylation status of histones in response to HDAC inhibitors (Jin and Scotto, 1998;El-Osta et al, 2002;Baker et al, 2005;Tabe et al, 2006;El-Khoury et al, 2007;Kim et al, 2008;Hauswald et al, 2009;Kim et al, 2009;Valdez et al, 2016;You et al, 2019a;You et al, 2019b). Such association confirmed that HDAC inhibitors did in fact prevent the de-acetylation of histone proteins.…”

“…The up-regulatory effects of cyclic peptides on MDR1 regulation were also observed in vivo. Our recent study showed that apicidin is capable of altering the transport properties of the normal mouse brain (alongside increased levels of acetylated histone H3K9/14 protein), but in a region-specific manner (You et al, 2019a). A 7-day intraperitoneal injection of apicidin in C57BL/6 mice moderately, yet significantly, increased Mdr1 protein expression in the striatum, but not in the cortex, the midbrain, or the hippocampus.…”

“…A study by showed that there were dose-dependent increases in acetylated histone proteins that correlated with induction of MDR1 protein . Also, VPA-and apicidin-mediated up-regulation of Mdr1 and Bcrp protein in different regions of mouse brains was accompanied by increases in acetylated histone H3 proteins (You et al, 2019a). Valdez and coworkers (2016) showed that the histone acetylation was observed earlier than the induction of MDR1, suggesting that acetylation of histones was a preceding event for MDR1 induction (Valdez et al, 2016).…”

Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk

“…Concerning histone post-translational modifications, exposure to valproate increased acetylation of histone H4 in the ABCG2 promoter in CMK cells as well as ABCG2 mRNA levels [194]. A recent study demonstrated that treatment with histone deacetylase elicits brain region-specific enhancement of histone H3 acetylation and upregulation of ABCG2 transporter in mice [195].…”