title: Naringenin protects against isoniazid- and rifampicin-induced apoptosis in hepatic injury.
abstract: OBJECTIVE
  To explore the protective effects and mechanisms of naringenin (NRG) on hepatic injury induced by isoniazid (INH) and rifampicin (RIF).
  
  
  METHODS
  Male mice were randomly divided into four groups and treated for 14 d as follows: normal control group was administered intragastrically with normal saline solution alone; model group was administered intragastrically with INH (100 mg/kg) and RIF (100 mg/kg); low- and high-dosage NRG pretreatment groups were administered intragastrically with different doses of NRG (50 or 100 mg/kg) 2 h before INH and RIF challenge. Mice were killed 16 h after the last dose of drug treatment to determine activity of serum transaminases. Oxidative stress was evaluated by measuring hepatic glutathione (GSH) and superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Histopathological changes in hepatic tissue were observed under the optical microscope. Hepatocyte apoptosis was measured by TUNEL assay and caspase-3 activation. Expression of Bcl-2 and Bax in liver was determined by western blot.
  
  
  RESULTS
  Both low- and high-dosage NRG pretreatment obviously alleviated serum levels of alanine aminotransferase and aspartate aminotransferase, liver index, hepatic MDA content, and increased hepatic GSH content and SOD activity compared with the INH and RIF-treated group (44.71 ± 8.15 U/L, 38.22 ± 6.64 U/Lvs58.15 ± 10.54 U/L; 98.36 ± 14.78 U/L, 92.41 ± 13.59 U/Lvs133.05 ± 19.36 U/L; 5.34% ± 0.26%, 4.93% ± 0.25%vs5.71% ± 0.28%; 2.76 ± 0.67 nmol/mgprot, 2.64 ± 0.64 nmol/mgprotvs4.49 ± 1.12 nmol/mgprot; 5.91 ± 1.31 mg/gprot, 6.42 ± 1.42 mg/gprotvs3.11 ± 0.73 mg/gprot; 137.31 ± 24.62 U/mgprot, 148.83 ± 26.75 U/mgprotvs102.34 ± 19.22 U/mgprot; allP< 0.01 or 0.05). Histopathological evaluation showed obvious necrosis and inflammatory cell infiltration in liver of mice administered INH and RIF; however, mice pretreated with NRG showed minor hepatic injury. In addition, INH and RIF resulted in hepatocyte apoptosis, and NRG pretreatment dramatically suppressed INH- and RIF-induced hepatocytes apoptosis. Furthermore, NRG-mediated anti-apoptotic effects seemed to be in connection with its regulation of Bax and Bcl-2 protein expression in hepatic tissue.
  
  
  CONCLUSIONS
  NRG might attenuate INH- and RIF-induced hepatic injuryviasuppression of oxidative stress and hepatocyte apoptosis.
authors.affiliation: Chao Wang, Yan-Xiang Zhang, Hao Nie, Kan Li, Department of Laboratory Medicine, Medical School, Yangtze University, Jingzhou 434023, Hubei Province, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Chao Wang, Yan-Xiang Zhang, Hao Nie, Kan Li, Department of Laboratory Medicine, Medical School, Yangtze University, Jingzhou 434023, Hubei Province, China.
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Fan
authors.affiliation: Chao Wang, Yan-Xiang Zhang, Hao Nie, Kan Li, Department of Laboratory Medicine, Medical School, Yangtze University, Jingzhou 434023, Hubei Province, China.
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Chao Wang, Yan-Xiang Zhang, Hao Nie, Kan Li, Department of Laboratory Medicine, Medical School, Yangtze University, Jingzhou 434023, Hubei Province, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Nie
authors.affiliation: Chao Wang, Yan-Xiang Zhang, Hao Nie, Kan Li, Department of Laboratory Medicine, Medical School, Yangtze University, Jingzhou 434023, Hubei Province, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Li
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection; D004195:Disease Models, Animal; D044950:Flavanones / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007538:Isoniazid; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012293:Rifampin; D013482:Superoxide Dismutase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; C494827:Bax protein, mouse; D015415:Biomarkers; D044950:Flavanones; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005978:Glutathione; C005273:naringenin; D007538:Isoniazid; D012293:Rifampin
keywords: Apoptosis; Hepatic injury; Isoniazid; Naringenin; Oxidative stress; Rifampicin