title: Therapeutic efficacy of Wuzhi tablet (Schisandra sphenanthera Extract) on acetaminophen-induced hepatotoxicity through a mechanism distinct from N-acetylcysteine.
abstract: Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Yiming
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Huasen
authors.initials: H
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G).
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yi.W., H.T., H.Z., Yo.W., M.H., H.B.); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (P.C.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.Q., F.J.G) bihchang@mail.sysu.edu.cn.
authors.forename: Huichang
authors.initials: H
authors.lastname: Bi
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000111:Acetylcysteine / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D032141:Schisandra / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D013607:Tablets / Q000494:pharmacology*
chemical_list: D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D013607:Tablets; C582515:wuzhi; D000082:Acetaminophen; D005978:Glutathione; D000111:Acetylcysteine