Journal
FOOD AND CHEMICAL TOXICOLOGY
Volume 58, Issue -, Pages 495-505Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2013.04.039
Keywords
Triptolide; Hepatotoxicity; Microarray analysis; Gene expression; Toxicogenomics
Categories
Funding
- National Natural Science Foundation of China [81173651]
- Specific Fund for Public Interest Research of Traditional Chinese Medicine, Ministry of Finance [200707008]
- 111 Project [111-2-07]
- Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Educational Institutions
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Triptolide (TP), a major component of TWHF, is widely used to treat rheumatoid arthritis, systemic lupus erythematosus, nephritis and leprosy. However, its clinical use is limited by hepatotoxicity. To further elucidate the underlying mechanism of its hepatotoxic effects, hepatic gene expression profiles were analyzed. TP (1000 and 300 mu g/kg) was orally administered to Wistar rats for 14 days. Current study indicated that female rats were more sensitive to TP-induced hepatotoxicity than males. Genome-wide microarray analyses identified 3329 differentially expressed genes in liver of female rats. Analyses of these genes identified over-represented functions associated with insulin signaling pathway, glucose metabolism, cell cycle, oxidative stress and apoptosis, which were consistent with the results of significant increase of Caspase-3 activity and reduction of serum glucose, GSH/GSSG ratio, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, liver glycogen. In addition, it was observed for the first time that glucocorticoids and IGF1 might get involved in TP-induced hepatotoxicity. These data suggest that TP treatment could alter the hepatic redox status, reduce serum glucose and induce hepatocyte apoptosis, consistent with the differential expression of genes involved in insulin signaling pathway, glucose metabolism pathway and cell stress pathway, all of which might contribute to the overall TP-induced hepatotoxicity. (C) 2013 Elsevier Ltd. All rights reserved.
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