Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Dr., 5038a Malott Hall, Lawrence, KA 66045, USA.
J Pharmacol Exp Ther. 2010 Nov;335(2):342-50. doi: 10.1124/jpet.110.171744. Epub 2010 Aug 18.
Long-term treatment of patients with the macrolide antibiotic and prototypical activator of pregnane X receptor (PXR) rifampicin (Rif) inhibits the inflammatory response in liver. We show here that activation of the inflammatory response in hepatocytes strongly modulates SUMOylation of ligand-bound PXR. We provide evidence that the SUMOylated PXR contains SUMO3 chains, and feedback represses the immune response in hepatocytes. This information represents the first step in developing novel pharmaceutical strategies to treat inflammatory liver disease and prevent adverse drug reactions in patients experiencing acute or systemic inflammation. These studies also provide a molecular rationale for constructing a novel paradigm that uniquely defines the molecular basis of the interface between PXR-mediated gene activation, drug metabolism, and inflammation.
大环内酯类抗生素和典型的孕烷 X 受体 (PXR) 激动剂利福平（Rif）的长期治疗可抑制肝脏的炎症反应。我们在此表明，肝实质细胞中炎症反应的激活强烈调节配体结合的 PXR 的 SUMO 化。我们提供的证据表明，SUMO 化的 PXR 含有 SUMO3 链，并反馈抑制肝实质细胞中的免疫反应。这些信息代表了开发治疗炎症性肝病和预防急性或全身性炎症患者发生药物不良反应的新型药物策略的第一步。这些研究还为构建一个独特定义 PXR 介导的基因激活、药物代谢和炎症之间界面的分子基础的新范例提供了分子依据。
