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.
Highlights
MethodsAll animals were maintained under standard conditions with lights on from 7:00 to 19:00 at 25 ± 1 ◦C and a relative humidity of 50% ± 5%
Liver fibrosis is a reversible wound-healing response to acute or chronic hepatocellular injury [1]
It is well accepted that CCl4 is metabolized by cytochrome p450 (CYP2E1 isoform) into the hepatotoxic radicals trichloromethyl CCl3 and Cl3COO that covalently bind to cell constituents leading to chain lipid peroxidation
Summary
All animals were maintained under standard conditions with lights on from 7:00 to 19:00 at 25 ± 1 ◦C and a relative humidity of 50% ± 5%. The animals were used in experiments after two days of adaptive feed and were housed at the animal facility of the Pharmacological Animal Medicine Center, College of Basic Medicine, Beijing University of Chinese Medicine, Beijing, China. Principles of laboratory animal care were followed and all experiments were carried out in accordance with the “Regulation for the Administration of Affairs Concerning Experimental Animals” (State Council of China, 1988). The Animal Care and Use Committee is the School of Chinese Pharmacy, Beijing University of Chinese Medicine (Date: 22 March 2015; No.: 201503-22)
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