title: Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration.
abstract: Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration.
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Fan
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Huasen
authors.initials: H
authors.lastname: Tan
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 bihchang@mail.sysu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 bihchang@mail.sysu.edu.cn.
authors.forename: Huichang
authors.initials: H
authors.lastname: Bi
mesh_terms: D000082:Acetaminophen / Q000378:metabolism; D065767:Activation, Metabolic; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016227:Benzoquinones / Q000378:metabolism; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D020134:Catalytic Domain; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D034242:Cyclooctanes / Q000737:chemistry / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D019610:Cytoprotection; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007097:Imines / Q000378:metabolism; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D015415:Biomarkers; D034242:Cyclooctanes; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004149:Dioxoles; D004365:Drugs, Chinese Herbal; D007097:Imines; D017705:Lignans; D008565:Membrane Proteins; D000082:Acetaminophen; C033585:schizandrol B; D019392:Cytochrome P-450 CYP2E1; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione
keywords: acetaminophen; bioactivation; liver injury; liver regeneration; schisandrol B