Xiang Hongjun, Han Yaotian, Zhang Yuzhong, Yan Wenqiang, Xu Bing, Chu Fuhao, Xie Tianxin, Jia Menglu, Yan Mengmeng, Zhao Rui, Wang Penglong, Lei Haimin
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
Department of Pathology, Beijing University of Chinese Medicine, Beijing 100102, China.
Int J Mol Sci. 2017 Mar 6;18(3):553. doi: 10.3390/ijms18030553.
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 (IC = 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 ( < 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 ( < 0.05). The acute toxicity test showed that LD 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 LD 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 (C = 8.18 ± 0.66 μg/mL) was 10 ± 2.19 h; the elimination half-life and area under the concentration-time curve from = 0 to the last time of Oxy-Di-OA was 2.19 h and 90.21 μg·h/mL, respectively.
一种新型保肝齐墩果酸衍生物，3-氧代乌苏-9(11),12-二烯-28-酸（Oxy-Di-OA）已见报道。在先前的研究中，我们发现Oxy-Di-OA具有抗乙肝病毒（HBV）活性（IC = 3.13 µg/mL）。值得注意的是，在抑制病毒复制率反弹方面，它优于拉米夫定。此外，Oxy-Di-OA在体内也表现出良好的抗HBV活性。一些研究表明，肝纤维化可能与HBV基因突变有关。此外，Oxy-Di-OA的抗肝纤维化活性尚未得到研究。因此，我们评估了Oxy-Di-OA对四氯化碳（CCl₄）诱导的大鼠肝损伤的保护作用。每日腹腔注射Oxy-Di-OA可预防CCl₄诱导的肝纤维化的发展，组织学研究和免疫组织化学分析证实了这一点。整个实验方案持续9周。Oxy-Di-OA显著抑制血浆天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平的升高（<0.05）。此外，Oxy-Di-OA可抑制转化生长因子β1（TGF-β1）的表达。值得注意的是，高剂量组的Oxy-Di-OA在改善肝功能方面优于联苯双酯。与模型组相比，高剂量组和低剂量组的Oxy-Di-OA均可显著降低肝脏和脾脏指数（<0.05）。急性毒性试验表明，通过小鼠腹腔注射，Oxy-Di-OA的半数致死量（LD）及其95%置信区间（CIs）值分别为714.83 mg/kg和639.73 - 798.73 mg/kg。通过小鼠灌胃，Oxy-Di-OA的LD值超过2000 mg/kg。此外，还建立并验证了一种简单快速的高效液相色谱-紫外（HPLC-UV）方法，用于研究该化合物的药代动力学特征。单次口服给药后，Oxy-Di-OA达到峰浓度（C = 8.18 ± 0.66 μg/mL）的时间为10 ± 2.19 h；消除半衰期以及Oxy-Di-OA从t = 0至最后一次的浓度-时间曲线下面积分别为2.19 h和90.21 μg·h/mL。
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