Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey (D.Y.); Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, Florida (J.R.R.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey (L.M.A.).
Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey (D.Y.); Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, Florida (J.R.R.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey (L.M.A.)
Drug Metab Dispos. 2020 Jun;48(6):459-480. doi: 10.1124/dmd.119.089953. Epub 2020 Mar 19.
Multidrug resistance protein 1 (MDR1, , P-glycoprotein) and breast cancer resistance protein (BCRP, ) are key efflux transporters that mediate the extrusion of drugs and toxicants in cancer cells and healthy tissues, including the liver, kidneys, and the brain. Altering the expression and activity of MDR1 and BCRP influences the disposition, pharmacodynamics, and toxicity of chemicals, including a number of commonly prescribed medications. Histone acetylation is an epigenetic modification that can regulate gene expression by changing the accessibility of the genome to transcriptional regulators and transcriptional machinery. Recently, studies have suggested that pharmacological inhibition of histone deacetylases (HDACs) modulates the expression and function of MDR1 and BCRP transporters as a result of enhanced histone acetylation. This review addresses the ability of HDAC inhibitors to modulate the expression and the function of MDR1 and BCRP transporters and explores the molecular mechanisms by which HDAC inhibition regulates these transporters. While the majority of studies have focused on histone regulation of MDR1 and BCRP in drug-resistant and drug-sensitive cancer cells, emerging data point to similar responses in nonmalignant cells and tissues. Elucidating epigenetic mechanisms regulating MDR1 and BCRP is important to expand our understanding of the basic biology of these two key transporters and subsequent consequences on chemoresistance as well as tissue exposure and responses to drugs and toxicants. SIGNIFICANCE STATEMENT: Histone deacetylase inhibitors alter the expression of key efflux transporters multidrug resistance protein 1 and breast cancer resistance protein in healthy and malignant cells.
多药耐药蛋白 1（MDR1， P-糖蛋白）和乳腺癌耐药蛋白（BCRP， ）是关键的外排转运蛋白，可介导癌细胞和包括肝脏、肾脏和大脑在内的健康组织中的药物和毒物的外排。改变 MDR1 和 BCRP 的表达和活性会影响化学物质的处置、药效学和毒性，包括许多常用的药物。组蛋白乙酰化是一种表观遗传修饰，可以通过改变基因组对转录调节剂和转录机制的可及性来调节基因表达。最近的研究表明，组蛋白去乙酰化酶（HDACs）的药理学抑制通过增强组蛋白乙酰化来调节 MDR1 和 BCRP 转运蛋白的表达和功能。这篇综述讨论了 HDAC 抑制剂调节 MDR1 和 BCRP 转运蛋白表达和功能的能力，并探讨了 HDAC 抑制调节这些转运蛋白的分子机制。虽然大多数研究都集中在耐药和敏感癌细胞中组蛋白对 MDR1 和 BCRP 的调节，但新出现的数据表明在非恶性细胞和组织中也存在类似的反应。阐明调节 MDR1 和 BCRP 的表观遗传机制对于扩展我们对这两个关键转运蛋白的基本生物学的理解以及随后对化学耐药性以及组织暴露和对药物和毒物的反应非常重要。
组蛋白去乙酰化酶抑制剂改变了健康和恶性细胞中关键外排转运蛋白多药耐药蛋白 1 和乳腺癌耐药蛋白的表达。
