title: Wuzhi tablet (Schisandra Sphenanthera extract) protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of NRF2-ARE and p53/p21 pathways.
abstract: Schisandra sphenanthera is widely used as a tonic and restorative in many countries to enhance the function of liver and other organs. Wuzhi tablet (WZ) is a preparation of an ethanol extract of Schisandra sphenanthera. Our previous study demonstrated that WZ exerted a protective effect toward acetaminophen (APAP)-induced hepatotoxicity. However, the molecular mechanisms of this protection remain unclear. This study aimed to determine what molecular pathways contributed to the hepatoprotective effects of WZ against APAP toxicity. Administration of WZ 3 days before APAP treatment significantly attenuated APAP hepatotoxicity in a dose-dependent manner and reduced APAP-induced JNK activation. Treatment with WZ resulted in potent inhibition of CYP2E1, CYP3A11, and CYP1A2 activities and then caused significant inhibition of the formation of the oxidized APAP metabolite N-acetyl-p-benzoquinone imine-reduced glutathione. The expression of NRF2 was increased after APAP and/or WZ treatment, whereas KEAP1 levels were decreased. The protein expression of NRF2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was significantly increased by WZ treatment. Furthermore, APAP increased the levels of p53 and its downstream gene p21 to trigger cell cycle arrest and apoptosis, whereas WZ pretreatment could inhibit p53/p21 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, PCNA, and ALR to promote hepatocyte proliferation. This study demonstrated that WZ prevented APAP-induced liver injury by inhibition of cytochrome P450-mediated APAP bioactivation, activation of the NRF2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the p53, p21, cyclin D1, CDK4, PCNA, and ALR to facilitate liver regeneration after APAP-induced liver injury.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (X.F., Y.J., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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., Yo.W., H.T., H.Z., Yi. 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, Maryland (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; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D032141:Schisandra / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D013607:Tablets / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004365:Drugs, Chinese Herbal; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D020011:Protective Agents; D013607:Tablets; D016159:Tumor Suppressor Protein p53; C582515:wuzhi; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase