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Research ArticleArticle

Therapeutic Efficacy of Wuzhi Tablet (Schisandra sphenanthera Extract) on Acetaminophen-Induced Hepatotoxicity through a Mechanism Distinct from N-Acetylcysteine

Xiaomei Fan, Pan Chen, Yiming Jiang, Ying Wang, Huasen Tan, Hang Zeng, Yongtao Wang, Aijuan Qu, Frank J. Gonzalez, Min Huang and Huichang Bi
Drug Metabolism and Disposition March 2015, 43 (3) 317-324; DOI: https://doi.org/10.1124/dmd.114.062067
Xiaomei Fan
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)
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Pan Chen
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)
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Yiming Jiang
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)
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Ying Wang
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)
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Huasen Tan
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)
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Hang Zeng
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)
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Yongtao Wang
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)
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Aijuan Qu
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)
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Frank J. Gonzalez
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)
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Min Huang
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)
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Huichang Bi
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)
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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.

Footnotes

    • Received November 12, 2014.
    • Accepted December 22, 2014.
  • This work was supported by the Natural Science Foundation of China [Grants 81373470, 81320108027]; the Science and Technology Ministry of China [Grant: 2012ZX09506001-004]; and the Fundamental Research Fund for the Central Universities [No. 13ykpy08].

  • dx.doi.org/10.1124/dmd.114.062067.

  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 43 (3)
Drug Metabolism and Disposition
Vol. 43, Issue 3
1 Mar 2015
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Research ArticleArticle

Therapeutic Efficacy of Wuzhi Tablet on APAP-Induced Hepatotoxicity

Xiaomei Fan, Pan Chen, Yiming Jiang, Ying Wang, Huasen Tan, Hang Zeng, Yongtao Wang, Aijuan Qu, Frank J. Gonzalez, Min Huang and Huichang Bi
Drug Metabolism and Disposition March 1, 2015, 43 (3) 317-324; DOI: https://doi.org/10.1124/dmd.114.062067

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Research ArticleArticle

Therapeutic Efficacy of Wuzhi Tablet on APAP-Induced Hepatotoxicity

Xiaomei Fan, Pan Chen, Yiming Jiang, Ying Wang, Huasen Tan, Hang Zeng, Yongtao Wang, Aijuan Qu, Frank J. Gonzalez, Min Huang and Huichang Bi
Drug Metabolism and Disposition March 1, 2015, 43 (3) 317-324; DOI: https://doi.org/10.1124/dmd.114.062067
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