title: Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats.
abstract: The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB) drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF) were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.
authors.affiliation: State Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. twinsyuanxin@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. zhaomanman@imm.ac.cn.
authors.forename: Manman
authors.initials: M
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. sylviami@imm.ac.cn.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Mi
authors.affiliation: State Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. chenhui@imm.ac.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. shengli@imm.ac.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Sheng
authors.affiliation: State Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. yanli@imm.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects*; D015415:Biomarkers; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004579:Electron Transport; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; D001713:Biphenyl Compounds; D016207:Cytokines; D020011:Protective Agents; D017382:Reactive Oxygen Species; C477843:bicyclol; D019392:Cytochrome P-450 CYP2E1
keywords: CYP2E1; HGF; bicyclol; cytokines; isoniazid; mitochondrial dysfunction; oxidative stress; pyrazinamide; rifampicin