title: A New Oleanolic Acid Derivative against CCl₄-Induced Hepatic Fibrosis in Rats.
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 LD50and 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 LD50value 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 fromt= 0 to the last time of Oxy-Di-OA was 2.19 h and 90.21 μg·h/mL, respectively.
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. iloveygr@163.com.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Xiang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. han_yaotian@bucm.edu.cn.
authors.forename: Yaotian
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pathology, Beijing University of Chinese Medicine, Beijing 100102, China. zyz100102@126.com.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. ywq3226925@163.com.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yan
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. weichenxubing@126.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. chufhao@163.com.
authors.forename: Fuhao
authors.initials: F
authors.lastname: Chu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. xietx1993@163.com.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Xie
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. jml15001290933@126.com.
authors.forename: Menglu
authors.initials: M
authors.lastname: Jia
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. yanmengmeng@bucm.edu.cn.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Yan
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. zr1012@bucm.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. wpl581@126.com.
authors.forename: Penglong
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. hm_lei@126.com.
authors.forename: Haimin
authors.initials: H
authors.lastname: Lei
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity; D005260:Female; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C000617692:3-oxours-oleana-9(11), 12-dien-28-oic acid; D053773:Transforming Growth Factor beta1; D009828:Oleanolic Acid; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: acute toxic test; carbon tetrachloride-induced; histological study; liver fibrosis; oleanolic acid derivative; pharmacokinetic