1. Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity
- Author
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Dong, Huang, Ying-Yuan, Zhao, Rui-Min, Wang, Wei, Li, Fang-Yu, Yuan, Xue-Long, Yan, Xiao, Yang, Gui-Hua, Tang, Sheng, Yin, and Hui-Chang, Bi
- Subjects
Pharmacology ,Biological Products ,Mice ,Cholestasis ,Liver Diseases ,Pregnane X Receptor ,Animals ,Cytochrome P-450 CYP3A ,Humans ,Pharmacology (medical) ,General Medicine - Abstract
Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg
- Published
- 2021