Department of Nonclinical Development and Clinical Pharmacology, Revolution Medicines, Inc, Redwood City, CA, United States.
Department of ADME & Discovery Toxicology, Merck & Co., Inc, Rahway, NJ, United States.
Drug Metab Rev. 2022 Aug;54(3):318-330. doi: 10.1080/03602532.2022.2101662. Epub 2022 Aug 24.
The 24th North American International Society for the Study of Xenobiotics (ISSX) meeting, held virtually from September 13 to 17, 2021, embraced the theme of "Broadening Our Horizons." This reinforces a key mission of ISSX: striving to share innovative science related to drug discovery and development. Session speakers and the ISSX New Investigators Group, which supports the scientific and professional development of student and early career ISSX members, elected to highlight the scientific content presented during the captivating session titled, "Epigenetics in Drug Disposition & Drug Therapy." The impact genetic variation has on drug response is well established; however, this session underscored the importance of investigating the role of epigenetics in drug disposition and drug discovery. Session speakers, Drs. Ning, McClay, and Lazarus, detailed mechanisms by which epigenetic players including long non-coding RNA (lncRNAs), microRNA (miRNAs), DNA methylation, and histone acetylation can alter the expression of genes involved in pharmacokinetics, pharmacodynamics, and toxicity. Dr. Ning detailed current knowledge about miRNAs and lncRNAs and the mechanisms by which they can affect the expression of drug metabolizing enzymes (DMEs) and nuclear receptors. Dr. Lazarus discussed the potential role of miRNAs on UDP-glucuronosyltransferase (UGT) expression and activity. Dr. McClay provided evidence that aging alters methylation and acetylation of DMEs in the liver, affecting gene expression and activity. These topics, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are herein discussed, along with exciting future perspectives for epigenetics in drug disposition and drug discovery research.
第 24 届北美国际异生素研究学会(ISSX)会议于 2021 年 9 月 13 日至 17 日以虚拟形式举行,主题为“拓宽视野”。这一主题强化了 ISSX 的一个主要使命:努力分享与药物发现和开发相关的创新科学。会议演讲者和 ISSX 新调查员小组(该小组支持学生和早期职业 ISSX 成员的科学和专业发展)选择强调了题为“药物处置和药物治疗中的表观遗传学”的精彩会议中呈现的科学内容。遗传变异对药物反应的影响已得到充分证实;然而,本次会议强调了研究表观遗传学在药物处置和药物发现中的作用的重要性。演讲者 Ning 博士、McClay 博士和 Lazarus 博士详细介绍了表观遗传因子(包括长非编码 RNA(lncRNA)、microRNA(miRNA)、DNA 甲基化和组蛋白乙酰化)改变参与药代动力学、药效学和毒性的基因表达的机制。Ning 博士详细介绍了当前关于 miRNA 和 lncRNA 的知识,以及它们影响药物代谢酶(DMEs)和核受体表达的机制。Lazarus 博士讨论了 miRNA 对 UDP-葡萄糖醛酸转移酶(UGT)表达和活性的潜在作用。McClay 博士提供了证据表明,衰老改变了肝脏中 DME 的甲基化和乙酰化,影响了基因表达和活性。这些主题由专题研讨会组织者、演讲者和 ISSX 新调查员小组汇编,本文对其进行了讨论,并探讨了药物处置和药物发现研究中表观遗传学的令人兴奋的未来展望。