CGX, a multiple herbal drug, improves cholestatic liver fibrosis in a bile duct ligation-induced rat model Hyeong-Geug Kim a , Jong-Min Han a , Hye-Won Lee b , Jin-Seok Lee a , Seung-Wan Son c , Min-Kyong Choi a , Dong-Soo Lee c , Jing-Hua Wang d,e , Chang-Gue Son a,n a Liver and immunology research center, Daejeon Oriental Hospital of Oriental Medical Collage of Daejeon University, 22-5 Daehung-dong, Jung-gu, Daejeon, 301-724, Republic of Korea b TKM-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Republic of Korea c Department of Biomedical Engineering, College of Health Science, Korea University, Seongbuk-Gu, Seoul 136-703, Republic of Korea d Department of Internal Medicine, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Republic of Korea e Key Labortary of Xia’an Medicine, Ministry of Education, Anhui Province Key Laboratory of R&D of TCM, Hefei, Anhui Province, People’s Republic China article info Article history: Received 26 September 2012 Received in revised form 13 November 2012 Accepted 1 December 2012 Keywords: Liver fibrosis Bile duct ligation Traditional Korean herbal medicine Oxidative stress abstract Ethnopharmacologic relevance: CGX is a modification of a traditional herbal medicine that has been used for various liver disorders as a meaning of ‘‘cleaning the liver’’. The cholestatic liver disorders become prevalent. Back ground and aim: This study aimed to investigate the anti-hepatic fibrosis effects of CGX and its underlying mechanisms in a rat model of bile duct ligation (BDL). Materials and methods: BDL was conducted in SD rats except shame operation group. The rats were orally administrated with distilled water, CGX (25 or 50 mg/kg) or ursodeoxycholic acid (UDCA, 25 mg/kg) for two weeks. The pharmaceutical effects and mechanisms were analyzed in histopathology, biochemistry, oxidative stress/antioxidant biomarkers and hepatic fibrogenic cytokines levels. Results: BDL markedly elevated white blood cell (WBC) counts as well as changed subset proportions such as increased neutrophils and decreased lymphocytes in peripheral blood. BDL drastically elevated the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, and hepatic tissue levels of hydroxyproline and malondialdehyde (MDA), while it reduced the total glutathione (GSH) content and the activities of GSH-redox system enzymes such as GSH-peroxidase, GSH-reductase and GSH-S-transferase. These alterations were significantly attenuated by CGX treatment (mainly 50 mg/kg). CGX treatment normalized both the accumulation of collagen in hepatic tissue and the increased levels of profibrogenic cytokine including transforming growth factor-b1 (TGF-b1) and platelet- derived growth factor-BB (PDGF-BB). Moreover, CGX treatment enhanced interferon-gamma (IFN-g) expression compare to the BDL group at the protein and gene level. Conclusion: These results suggest that CGX exerts anti-hepatofibrotic effect in rat BDL model, and the responsible mechanisms involve the inhibition of hepatic fibrogenic cytokines and oxidative stress. & 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction CGX is a modified herbal drug based on a traditional hepa- totherapeutic formula in Korea. This herbal formula has the meaning of ‘‘cleaning the liver’’ and was initially originated from a ancient medical book, Donguibogam, which was designated as a UNESCO documentary heritage in 2009 (UNESCO, 2009). CGX has been used for patients suffering from chronic viral hepatitis, hepatic fibrosis and cirrhosis, and alcoholic liver disorders in the Republic of Korea (Choi et al., 2006; Shin et al., 2009; Son et al., 2003). Previously, we presented scientific evidence for the hepa- totherapeutic effects and antioxidant properties of CGX in animal models of hepatic injury induced by carbon tetrachloride (CCl 4 ; Hu et al., 2008), dimethylnitrosamine (DMN; Wang et al., 2010a)), and thioacetamide (TAA); (Kwak et al., 2011). Meanwhile, hepatic fibrosis is a serious complication caused by chronic hepatic injuries including metabolic, viral infection, toxic agent invasion, alcohol abuse, genetic disease and choles- tasis. Previous studies have shown that oxidative stressors, such as reactive oxygen species (ROS), can cause the damage in hepatocytes and induce accumulation of excessive extracellular Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/jep Journal of Ethnopharmacology 0378-8741/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2012.12.005 n Corresponding author at: Liver and immunology research center, Daejeon Oriental Hospital of Daejeon University, 22-5 Daehung-dong, Jung-gu, Daejeon, 301-724, Republic of Korea. Tel.: þ82 42 229 6484; fax: þ82 42 257 6398. E-mail address: ckson@dju.kr (C.-G. Son). Please cite this article as: Kim, H.-G., et al., CGX, a multiple herbal drug, improves cholestatic liver fibrosis in a bile duct ligation- induced rat model. Journal of Ethnopharmacology (2012), http://dx.doi.org/10.1016/j.jep.2012.12.005i Journal of Ethnopharmacology ] (]]]]) ]]]–]]]