Quantitative proteomics analysis of Fructus Psoraleae-induced hepatotoxicity in rats  

作　　者：LI Zhi-Jian Abudumijiti Abulizi XU Deng-Qiu Youlidouzi Maimaiti Silafu Aibai JIANG Zhen-Zhou ZHAO Guo-Lin WANG Tao Aiximujiang Refukati Zulikaer Maimaiti Yiliyaer Simayi CAO Chun-Yu ZHANG Lu-Yong 

机构地区：[1]Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University,Nanjing 210009,China [2]'Department of Toxicology Laboratory,Xinjiang Institute of Traditional Uyghur Medicine,Urumqi 830049,China [3]State Key Laboratory of Natural and Biomimetic Drugs,Department of Pharmacology,School of Basic Medical Sciences,Peking University,Beijing 100191,China [4]Center for Drug Screening and Pharmacodynamics Evaluation,School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou 510006,China [5]Key Laboratory of Drug Quality Control and Pharmacovigilance,China Pharmaceutical University,Nanjing 210009,China [6]Jiangsu Center for Pharmacodynamics Research and Evaluation,China Pharmaceutical University,Nanjing 210009,China [7]State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China [8]K Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China

出　　处：《Chinese Journal of Natural Medicines》2020年第2期123-137,共15页中国天然药物（英文版）

基　　金：supported by the the National Key Research and Development Program, Specialized Research on Modernization of TCM (Nos. 2018YFC1708006 and 2018YFC1708003);National Major New Drug Creation Special Project “National Drug New Varieties Research and Development and Its Key Innovative Technology Topics” (No. 2017ZX09301060-005);the National Natural Science Foundation of China (No. 81320108029);Tianshan Cedar Plan (No. 2018XS21);National “Major Scientific and Technological Special Project for Significant New Drugs Creation” Project (No. 2015ZX09501004-002-004);Specific Fund for Pub-lic Interest Research of Traditional Chinese Medicine, Ministry of Finance of China (No. 201507004-002)。

摘　　要：Fructus Psoraleae,which is commonly consumed for the treatment of osteoporosis,bone fracture,and leucoderma,induces liver injury.This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae(EEFP)-induced liver injury in rats.EEFP(1.35,1.80,and 2.25 g·kg^–1)was administrated to Sprague Dawley(SD)rats for 30 d.We measured liver chemistries,histopathology,and quantitative isobaric tags for relative and absolute quantitation(iTRAQ)-based protein profiling.EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion,bile flow rate,and liver histopathology.iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats.Among these proteins,81 were upregulated and 32 were downregulated in the treatment group.KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450,glutathione metabolism,glycerolipid metabolism,and bile secretion were enriched with differentially expressed proteins.The expression of key proteins related to the farnesoid X receptor(FXR),i.e.,the peroxisome proliferators-activated receptor alpha(PPAR-α),were downregulated,and multidrug resistance-associated protein 3(MRP3)was upregulated in the EEFP-treated rats.Our results provide evidence that EEFP may induce hepatotoxicity through various pathways.Furthermore,our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.Fructus Psoraleae, which is commonly consumed for the treatment of osteoporosis, bone fracture, and leucoderma, induces liver injury. This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae(EEFP)-induced liver injury in rats. EEFP(1.35, 1.80, and 2.25 g·kg–1) was administrated to Sprague Dawley(SD) rats for 30 d. We measured liver chemistries, histopathology, and quantitative isobaric tags for relative and absolute quantitation(iTRAQ)-based protein profiling. EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion, bile flow rate, and liver histopathology. iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats. Among these proteins, 81 were upregulated and 32 were downregulated in the treatment group. KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450, glutathione metabolism, glycerolipid metabolism, and bile secretion were enriched with differentially expressed proteins. The expression of key proteins related to the farnesoid X receptor(FXR), i.e., the peroxisome proliferators-activated receptor alpha(PPAR-α), were downregulated, and multidrug resistance-associated protein 3(MRP3) was upregulated in the EEFP-treated rats.Our results provide evidence that EEFP may induce hepatotoxicity through various pathways. Furthermore, our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.

关 键 词：HEPATOTOXICITY ITRAQ ANALYSIS Fructus Psoraleae FXR MRP3 

分 类 号：R965[医药卫生—药理学]