title: Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.
abstract: Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver.
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: He
authors.initials: H
authors.lastname: Zhu
authors.affiliation: College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300222, PR China.
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Long
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Clinical Pharmacology Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: Xiu-Yang
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: Jin-Di
authors.initials: JD
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Fang
authors.affiliation: Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.|Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
authors.forename: Song-Lin
authors.initials: SL
authors.lastname: Li
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D005894:Panax / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001647:Bile Acids and Salts; D010936:Plant Extracts; D003520:Cyclophosphamide; D005978:Glutathione