Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Drug Metab Rev. 2013 Feb;45(1):79-100. doi: 10.3109/03602532.2012.740049. Epub 2012 Dec 5.
Xenobiotic compounds undergo a critical range of biotransformations performed by the phase I, II, and III drug-metabolizing enzymes. The oxidation, conjugation, and transportation of potentially harmful xenobiotic and endobiotic compounds achieved by these catalytic systems are significantly regulated, at the gene expression level, by members of the nuclear receptor (NR) family of ligand-modulated transcription factors. Activation of NRs by a variety of endo- and exogenous chemicals are elemental to induction and repression of drug-metabolism pathways. The master xenobiotic sensing NRs, the promiscuous pregnane X receptor and less-promiscuous constitutive androstane receptor are crucial to initial ligand recognition, jump-starting the metabolic process. Other receptors, including farnesoid X receptor, vitamin D receptor, hepatocyte nuclear factor 4 alpha, peroxisome proliferator activated receptor, glucocorticoid receptor, liver X receptor, and RAR-related orphan receptor, are not directly linked to promiscuous xenobiotic binding, but clearly play important roles in the modulation of metabolic gene expression. Crystallographic studies of the ligand-binding domains of nine NRs involved in drug metabolism provide key insights into ligand-based and constitutive activity, coregulator recruitment, and gene regulation. Structures of other, noncanonical transcription factors also shed light on secondary, but important, pathways of control. Pharmacological targeting of some of these nuclear and atypical receptors has been instituted as a means to treat metabolic and developmental disorders and provides a future avenue to be explored for other members of the xenobiotic-sensing NRs.
外源性化合物经历了一系列关键的生物转化，这些转化由 I 相、II 相和 III 相药物代谢酶完成。这些催化系统对潜在有害的外源性和内源性化合物进行氧化、结合和转运，其在基因表达水平上受到核受体 (NR) 家族配体调节转录因子的显著调控。各种内源性和外源性化学物质对 NR 的激活是诱导和抑制药物代谢途径的基础。NR 中的主要外源性物质感应受体，即混杂的孕烷 X 受体和不那么混杂的组成型和雄激素受体，对于初始配体识别至关重要，为代谢过程提供了启动。其他受体，包括法尼醇 X 受体、维生素 D 受体、肝细胞核因子 4α、过氧化物酶体增殖物激活受体、糖皮质激素受体、肝 X 受体和 RAR 相关孤儿受体，虽然不直接与混杂的外源性物质结合，但在调节代谢基因表达方面显然发挥着重要作用。涉及药物代谢的 9 种 NR 中配体结合域的晶体结构研究提供了关于基于配体的和组成型活性、共激活因子募集和基因调控的关键见解。其他非典型转录因子的结构也揭示了次要但重要的控制途径。一些核受体和非典型受体的药理学靶向已被作为治疗代谢和发育障碍的一种手段，并为外源性物质感应 NR 的其他成员提供了未来的探索途径。
