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Int. J. Mol. Sci. 2017, 18(3), 553;

A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats

School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China
Department of Pathology, Beijing University of Chinese Medicine, Beijing 100102, China
Authors to whom correspondence should be addressed.
Academic Editors: Rolf Teschke and Gaby Danan
Received: 7 January 2017 / Revised: 21 February 2017 / Accepted: 26 February 2017 / Published: 6 March 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
PDF [2024 KB, uploaded 8 March 2017]


A novel hepatoprotective oleanolic acid derivative, 3-oxours-oleana-9(11), 12-dien-28-oic acid (Oxy-Di-OA), has been reported. In previous studies, we found that Oxy-Di-OA presented the anti-HBV (Hepatitis B Virus) activity (IC50 = 3.13 µg/mL). Remarkably, it is superior to lamivudine in the inhibition of the rebound of the viral replication rate. Furthermore, Oxy-Di-OA showed good performance of anti-HBV activity in vivo. Some studies showed that liver fibrosis may affiliate with HBV gene mutations. In addition, the anti-hepatic fibrosis activity of Oxy-Di-OA has not been studied. Therefore, we evaluated the protective effect of Oxy-Di-OA against carbon tetrachloride (CCl4)-induced liver injury in rats. Daily intraperitoneally administration of Oxy-Di-OA prevented the development of CCl4-induced liver fibrosis, which was evidenced by histological study and immunohistochemical analysis. The entire experimental protocol lasted nine weeks. Oxy-Di-OA significantly suppressed the increases of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (p < 0.05). Furthermore, Oxy-Di-OA could prevent expression of transforming growth factor β1 (TGF-β1). It is worth noting that the high-dose group Oxy-Di-OA is superior to bifendate in elevating hepatic function. Compared to the model group, Oxy-Di-OA in the high-dose group and low-dose group can significantly reduce the liver and spleen indices (p < 0.05). The acute toxicity test showed that LD50 and a 95% confidence interval (CIs) value of Oxy-Di-OA were 714.83 mg/kg and 639.73–798.73 mg/kg via intraperitoneal injection in mice, respectively. The LD50 value of Oxy-Di-OA exceeded 2000 mg/kg via gavage in mice. In addition, a simple and rapid high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of Oxy-Di-OA (Cmax = 8.18 ± 0.66 μg/mL) was 10 ± 2.19 h; the elimination half-life and area under the concentration-time curve from t = 0 to the last time of Oxy-Di-OA was 2.19 h and 90.21 μg·h/mL, respectively. View Full-Text
Keywords: oleanolic acid derivative; carbon tetrachloride-induced; liver fibrosis; histological study; acute toxic test; pharmacokinetic oleanolic acid derivative; carbon tetrachloride-induced; liver fibrosis; histological study; acute toxic test; pharmacokinetic

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Xiang, H.; Han, Y.; Zhang, Y.; Yan, W.; Xu, B.; Chu, F.; Xie, T.; Jia, M.; Yan, M.; Zhao, R.; Wang, P.; Lei, H. A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats. Int. J. Mol. Sci. 2017, 18, 553.

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