University of Kansas Medical Center, Kansas City, KS 66160, USA; Zunyi Medical College, Zunyi 563003, China.
Toxicol Appl Pharmacol. 2013 Nov 1;272(3):816-24. doi: 10.1016/j.taap.2013.08.003. Epub 2013 Aug 13.
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 (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα 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.
齐墩果酸（OA）是一种广泛存在于植物中的三萜类化合物。OA 具有抗肝毒性作用。低剂量 OA 具有肝保护作用，而高剂量和长期使用 OA 则会导致肝损伤。本研究对 OA 诱导的小鼠肝损伤进行了特征描述。成年 C57BL/6 小鼠每天腹腔注射 0、22.5、45、90 和 135mg/kg 的 OA，连续 5 天，当剂量达到 90mg/kg 及以上时，观察到肝损伤，表现为血清丙氨酸氨基转移酶和碱性磷酸酶活性升高，血清总胆红素升高，以及肝组织病理学变化。OA 诱导的胆汁淤积性肝损伤进一步表现为血清未结合和结合胆汁酸（BAs）显著增加。基因和蛋白表达分析表明，OA 处理的小鼠肝脏通过抑制 BA 生物合成酶基因（Cyp7a1、8b1、27a1 和 7b1）、降低 BA 摄取转运体（Ntcp 和 Oatp1b2）和增加 BA 外排转运体（Ostβ）来防止 BA 积累，从而产生适应性反应。OA 增加了 Nrf2 及其靶基因 Nqo1 的表达，但降低了 AhR、CAR 和 PPARα 及其靶基因 Cyp1a2、Cyp2b10 和 Cyp4a10 的表达。OA 对 PXR 和 Cyp3a11 的影响较小。综上所述，本研究对 OA 诱导的肝损伤进行了特征描述，该损伤与改变的 BA 动态平衡有关，并提醒其潜在的毒性。
