Basic Sciences, Kansas City University of Medicine and Biosciences, Joplin, MO, USA.
Mol Cell Endocrinol. 2019 Apr 5;485:61-71. doi: 10.1016/j.mce.2019.02.002. Epub 2019 Feb 3.
The canonical effect of Pregnane X Receptor (PXR, NR1I2) agonism includes enhanced hepatic uptake and a concomitant increase in the first-pass metabolism and efflux of drugs in mammalian liver and intestine. In patients undergoing combination therapy, PXR-mediated gene regulation represents the molecular basis of numerous food-drug, herb-drug, and drug-drug interactions. Moreover, PXR activation promotes chemotherapeutic resistance in certain malignancies. Additional research efforts suggest that sustained PXR activation exacerbates the development of fatty liver disease. Additional metabolic effects of PXR activation in liver are the inhibition of fatty acid oxidation and gluconeogenesis. The identification of non-toxic and selective PXR antagonists is therefore of current research interest. Inhibition of PXR should decrease adverse effects, improve therapeutic effectiveness, and advance clinical outcomes in patients with cancer, fatty liver, and diabetes. This review identifies small molecule PXR antagonists described to date, discusses possible molecular mechanisms of inhibition, and seeks to describe the likely biomedical consequences of the inhibition of this nuclear receptor superfamily member.
pregnane X 受体 (PXR，NR1I2) 激动作用的典型效应包括增强肝脏摄取，并伴随哺乳动物肝脏和肠道中药物的首过代谢和外排增加。在接受联合治疗的患者中，PXR 介导的基因调节代表了许多食物-药物、草药-药物和药物-药物相互作用的分子基础。此外，PXR 的激活促进了某些恶性肿瘤的化疗耐药性。进一步的研究表明，持续的 PXR 激活会加剧脂肪肝疾病的发展。PXR 激活在肝脏中的其他代谢效应是抑制脂肪酸氧化和糖异生。因此，寻找非毒性和选择性的 PXR 拮抗剂是当前研究的热点。抑制 PXR 应该可以减少不良反应，提高癌症、脂肪肝和糖尿病患者的治疗效果和临床转归。本综述确定了迄今为止描述的小分子 PXR 拮抗剂，讨论了可能的抑制分子机制，并试图描述抑制该核受体超家族成员的可能的生物医学后果。
