title: Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats.
abstract: 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 μg/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.
authors: Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Jiaying
authors: J
authors: Wang
authors: Zhenzhou
authors: Z
authors: Jiang
authors: Jinzi
authors: J
authors: Ji
authors: Xinzhi
authors: X
authors: Wang
authors: Tao
authors: T
authors: Wang
authors: Yun
authors: Y
authors: Zhang
authors: Ting
authors: T
authors: Tai
authors: Mi
authors: M
authors: Chen
authors: Lixin
authors: L
authors: Sun
authors: Xia
authors: X
authors: Li
authors: Luyong
authors: L
authors: Zhang
mesh_terms: D000818:Animals; D004224:Diterpenes / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D005260:Female; D020869:Gene Expression Profiling; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010616:Phenanthrenes / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D010616:Phenanthrenes; C001899:triptolide
keywords: A; ALP; ALT; APC/C; AST; G; GO; GR; Gene expression; Glu; Hepatotoxicity; IGF-I; IGFBP-1; Microarray analysis; TBA; TBIL; TC; TG; TP; TWHF; Toxicogenomics; Tripterygium wilfondii Hook F; Triptolide; alanine aminotransferase; albumin; alkaline phosphatase; anaphase-promoting complex/cyclosome; aspartate aminotransferase; gene ontology; globulin; glucocorticoid recepto; glucose; insulin-like growth factor 1; insulin-like growth factor-binding protein-1; total bile acid; total bilirubin; total cholesterol; total protein; triglyceride; triptolide; γ-GGT; γ-glutamyl transpeptidase