Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice
详细信息 查看全文
- 作者：Jie Liu ; Yuan-Fu Lu ; Youcai Zhang ; Kai Connie Wu ; Fang Fan ; Curtis D. Klaassen
- 关键词：OA ; oleanolic acid ; ALT ; alanine aminotransferase ; UPLC-MS/MS ; ultra performance liquid chromatography tandem mass spectrometry ; Ntcp ; Na+-taurocholate co-transporting ploypeptide ; Oatp1b2 ; organic anion-transporting polypeptide 1b2 ; Bsep ; bile salt expor
- 刊名：Toxicology and Applied Pharmacology
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：272
- 期：3
- 页码：816-824
- 全文大小：1344 K
文摘
Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ost¦Â). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPAR¦Á along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential.