Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice

Abstract

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.

Low Dose of Oleanolic Acid Protects against Lithocholic Acid–Induced Cholestasis in Mice: Potential Involvement of Nuclear Factor-E2-Related Factor 2-Mediated Upregulation of Multidrug Resistance-Associated Proteins

“…; the highest dose (20 mg/kg) is a safe and effective dose, and no liver injury or cholestasis was observed. In addition, we focused on the effect of OA in bile acid output and noted Nrf2-mediated induction of Mrp2, Mrp3, and Mrp4 as the possible mechanism of hepatoprotection of OA, which was not presented in the studies by Liu et al (2013) and Lu et al (2013). Taken together, this suggests that, for the therapy of cholestasis, OA is a double-edged sword; at doses of 90 mg/kg and above, OA can cause apparent liver injury and cholestasis, whereas at doses below 22.5 mg/kg, especially at 20 mg/kg, OA can protect against LCA-induced cholestasis.…”

Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

“…The dose selection was based on previous reports from the literature. 16,28,29 Our results showed that OA-MVLs were more effective for inhibiting tumor growth ( Figure 9A) and prolonging survival times ( Figure 9B) in a dose-dependent manner, compared to the saline and OA solution. The enhanced antitumor activity of OA-MVLs may be due to the slow-release effect which was confirmed by both release profile in vitro and plasma pharmacokinetic studies in vivo.…”

“…16,28,29 All the animals were given an ip injection of 2 mL of different formulations mentioned, on every other day for 30 days, and their body weight was weighed at every other week. Moreover, all the animals were observed once daily for the signs of toxicities and twice daily for mortality.…”

“…The tumor-bearing mice were divided randomly into five groups (n=10) as follows: I, saline as control; II, OA solution; III, low-dose OA-MVLs, 25 mg/kg; IV, mediumdose OA-MVLs, 50 mg/kg; and V, high-dose OA-MVLs, 100 mg/kg. 16,28,29 On day 5 post-inoculation of cancer cells when the tumors reached a volume of 70-100 mm 3 , the treatments were initiated by ip injection with 500 μL of the solution mentioned. Meanwhile, every group was randomly divided into part A and part B with five mice each.…”

Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury

“…At higher doses, flavonoids have been reported to act as mutagens, prooxidants, and inhibitors of key enzymes involved in hormone metabolism [142]. Oleanolic acid, which is a known inducer of Nrf2 pathway, has been shown to cause cholestasis at higher doses [129, 143]. …”