The mechanism of Psoralen and Isopsoralen hepatotoxicity as revealed by hepatic gene expression profiling in SD rats

• Published in: Basic & clinical pharmacology & toxicology 2019-12, Vol.125 (6), p.527-535
• Main Authors: Song, Lei, Yu, Bin, Yang, Li, Wang, Zhao‐xin, Zhang, Yue, Yu, Ying‐li, Zhou, Kun
• Format: Article
• Language: English
• Subjects: Alanine; Alanine transaminase; Animals; Aspartate aminotransferase; Carcinogenesis; Carcinogens; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; CYP1A2 protein; Cytochrome; Cytochrome P450; Cytochromes P450; Endoplasmic reticulum; Ficusin - toxicity; Furocoumarins - toxicity; Gene expression; Gene Expression Profiling; Genes; GSTM1 protein; Hepatotoxicity; isopsoralen; Liver; Liver - drug effects; Liver - metabolism; Metabolism; Organic chemistry; Oxidoreductase; Psoralen; Random Allocation; rat; Rats; Rats, Sprague-Dawley; Ribonucleic acid; RNA; RNA, Messenger; Triglycerides; Xenobiotics
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.13287

Background The main bioactive components of Fructus psoraleae, such as psoralen and isopsoralen, are known to be hepatotoxic. However, its underlying mechanism is to be elucidated. Methods To address this, SD rats were randomly divided into control group, 60 mg/kg psoralen group and 60 mg/kg isopsoralen group. Blood was collected to detect serum biochemical indices. RNA was extracted from liver samples, and then, cDNA gene expression profiles were analysed. Results Psoralen administration significantly up‐regulated serum AST (aspartate aminotransferase) while addition of isopsoralen increased serum ALT (alanine aminotransferase), AST, TBA (total bile acid) and TG (total triglyceride) levels. A total of 172 differentially expressed genes (DEGs) were acquired between psoralen group and control group while 884 DEGs were screened between isopsoralen group and control group. Chemical Carcinogenesis and Metabolism of Xenobiotics by Cytochrome P450 were the two most significantly enriched pathways as revealed by DEGs. Liver was the most impacted organ, and endoplasmic reticulum was the most impacted organelle in subcellular level. Finally, some kinds of cancers and cytochrome p450 oxidoreductase deficiency were predicted. Taken together, psoralen and isopsoralen might cause hepatotoxicity mainly through cytochrome P450 metabolism of xenobiotics. Furthermore, Cyp1a1, Cyp1a2, Gstm1 and Akr7a3 worked as key genes in hepatotoxicity. Moreover, endoplasmic reticulum was the main target subcellular structure in hepatotoxicity induced by psoralen and isopsoralen.