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Int. J. Mol. Sci. 2017, 18(3), 553; doi:10.3390/ijms18030553

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

1
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China
2
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)
View Full-Text   |   Download PDF [2024 KB, uploaded 8 March 2017]   |  

Abstract

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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MDPI and ACS Style

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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