中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury

文献类型：期刊论文

作者Li, Guanting1; Hu, Yourong1; Zhao, Han1; Peng, Ziyu2; Shang, Xin3; Zhang, Jia1; Xie, Kunxin1; Li, Meiwei1; Zhou, Xiaohang1; Zhou, Qinyao1
刊名ADVANCED SCIENCE
出版日期2024-11-29
页码14
关键词benzbromarone drug-induced liver injury drug metabolism obesity PPAR gamma
DOI10.1002/advs.202409126
英文摘要Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug-induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti-gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity-specific DILI warrants further investigation. In this study, through a combined multi-omics, pharmacological, and pharmacokinetic approaches, it is found that BBR-induced obesity-specific DILI is primarily through the potentiation of peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPAR gamma agonism. This study demonstrates that a slow metabolism-driven amplification of hepatic PPAR gamma agonism mediates BBR-induced obesity-specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre-existing NAFLD in both clinical practice and drug discovery processes.
WOS关键词GENE-EXPRESSION ; PHARMACOKINETICS ; HYPERLIPIDEMIA ; ROSIGLITAZONE ; POSACONAZOLE ; TOXICITY ; DISEASE ; ENZYMES ; GOUT
资助项目National Natural Science Foundation of China ; Natural Science Foundation of Jiangsu Province[BK20211251] ; Natural Science Foundation of Jiangsu Province[BK20220149] ; State Key Laboratory of Drug Research[SIMM2205KF-13] ; [82270849] ; [82173882] ; [82322067] ; [81603169]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
WOS记录号WOS:001366159700001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/314789]  
专题新药研究国家重点实验室
通讯作者Xu, Zhijian; Liu, Jiali; Sun, Peng
作者单位1.Nanjing Med Univ, Wuxi Med Ctr, Dept Biochem & Mol Biol, Key Lab Human Funct Genom Jiangsu Prov,Wuxi People, Nanjing 211166, Peoples R China
2.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.China Pharmaceut Univ, Key Lab Drug Metab & Pharmacokinet, State Key Lab Nat Med, Nanjing 210009, Peoples R China
推荐引用方式
GB/T 7714		 Li, Guanting,Hu, Yourong,Zhao, Han,et al. Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury[J]. ADVANCED SCIENCE,2024:14.
APA Li, Guanting.,Hu, Yourong.,Zhao, Han.,Peng, Ziyu.,Shang, Xin.,...&Sun, Peng.(2024).Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury.ADVANCED SCIENCE,14.
MLA Li, Guanting,et al."Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury".ADVANCED SCIENCE (2024):14.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。