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Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice
Key Lab of Pharmacology, Zunyi Medical College, Zunyi 563003, China
University of Kansas Medical Center, Kansas City, KS 66160, USA
* Authors to whom correspondence should be addressed.
Received: 27 December 2012; in revised form: 25 February 2013 / Accepted: 27 February 2013 / Published: 7 March 2013
Abstract: Oleanolic acid (OA) is a triterpenoid and a fantastic molecule with many beneficial effects. However, high-doses and long-term use can produce adverse effects. This study aimed to characterize the hepatotoxic potential of OA. Mice were given OA at doses of 100–3,000 µmol/kg (45–1,350 mg/kg), po for 10 days, and the hepatotoxicity was determined by serum biochemistry, histopathology, and toxicity-related gene expression via real-time RT-PCR. Animal body weight loss was evident at OA doses of 1,000 µmol/kg and above. Serum alanine aminotransferase activities were increased in a dose-dependent manner, indicative of hepatotoxicity. Serum total bilirubin concentrations were increased, indicative of cholestasis. OA administration produced dose-dependent pathological lesions to the liver, including inflammation, hepatocellular apoptosis, necrosis, and feathery degeneration indicative of cholestasis. These lesions were evident at OA doses of 500 µmol/kg and above. Real-time RT-PCR revealed that OA produced dose-dependent increases in acute phase proteins (MT-1, Ho-1, Nrf2 and Nqo1), decreases in bile acid synthesis genes (Cyp7a1 and Cyp8b1), and decreases in liver bile acid transporters (Ntcp, Bsep, Oatp1a1, Oatp1b2, and Ostβ). Thus, the clinical use of OA and OA-type triterpenoids should balance the beneficial effects and toxicity potentials.
Keywords: oleanolic acid; oral administration; cholestasis; inflammation; bile acid synthesis; bile acid transporters
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MDPI and ACS Style
Lu, Y.-F.; Wan, X.-L.; Xu, Y.; Liu, J. Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice. Molecules 2013, 18, 3060-3071.
Lu Y-F, Wan X-L, Xu Y, Liu J. Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice. Molecules. 2013; 18(3):3060-3071.
Lu, Yuan-Fu; Wan, Xiao-Li; Xu, Yasha; Liu, Jie. 2013. "Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice." Molecules 18, no. 3: 3060-3071.