Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2016; 22(44): 9775-9783
Published online Nov 28, 2016. doi: 10.3748/wjg.v22.i44.9775
Naringenin protects against isoniazid- and rifampicin-induced apoptosis in hepatic injury
Chao Wang, Rui-Qin Fan, Yan-Xiang Zhang, Hao Nie, Kan Li
Chao Wang, Yan-Xiang Zhang, Hao Nie, Kan Li, Department of Laboratory Medicine, Medical School, Yangtze University, Jingzhou 434023, Hubei Province, China
Chao Wang, Hao Nie, Clinical and Molecular Immunology Research Center, Yangtze University, Jingzhou 434023, Hubei Province, China
Rui-Qin Fan, Department of Hepatic Disease, the Second Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China
Author contributions: Wang C and Fan RQ contributed equally to this work; Wang C designed the research and revised the manuscript; Fan RQ performed the experiments, analyzed the data and wrote the manuscript; Zhang YX, Nie H and Li K established the animal model and collected the data.
Supported by National Natural Science Foundation of China, No. 31502059; Education Department of Hubei Province, No. B2016039; Medical School of Yangtze University, No. YXYQ201406; and Clinical and Molecular Immunology Research Center of Yangtze University.
Institutional review board statement: This study was reviewed and approved by the Medical School of Yangtze University.
Institutional animal care and use committee statement: All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Yangtze University (Approval No. 20150148).
Conflict-of-interest statement: The authors report no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Chao Wang, Associate Professor, Department of Laboratory Medicine, Medical School, Yangtze University, 1 Nanhuan Road, Jingzhou 434023, Hubei Province, China. celful60@163.com
Telephone: +86-716-8062635 Fax: +86-716-8062635
Received: July 4, 2016
Peer-review started: July 6, 2016
First decision: August 29, 2016
Revised: September 11, 2016
Accepted: September 28, 2016
Article in press: September 28, 2016
Published online: November 28, 2016
Processing time: 144 Days and 22.8 Hours
Abstract
AIM

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/L vs 58.15 ± 10.54 U/L; 98.36 ± 14.78 U/L, 92.41 ± 13.59 U/L vs 133.05 ± 19.36 U/L; 5.34% ± 0.26%, 4.93% ± 0.25% vs 5.71% ± 0.28%; 2.76 ± 0.67 nmol/mgprot, 2.64 ± 0.64 nmol/mgprot vs 4.49 ± 1.12 nmol/mgprot; 5.91 ± 1.31 mg/gprot, 6.42 ± 1.42 mg/gprot vs 3.11 ± 0.73 mg/gprot; 137.31 ± 24.62 U/mgprot, 148.83 ± 26.75 U/mgprot vs 102.34 ± 19.22 U/mgprot; all P < 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.

CONCLUSION

NRG might attenuate INH- and RIF-induced hepatic injury via suppression of oxidative stress and hepatocyte apoptosis.

Keywords: Naringenin; Isoniazid; Rifampicin; Oxidative stress; Apoptosis; Hepatic injury

Core tip: Anti-tuberculosis drugs can cause drug-induced liver injury through a series of complex mechanisms. The main purposes of the study were to explore the effects of naringenin (NRG) on liver injury induced by isoniazid (INH) and rifampicin (RIF). Mice were administered intragastrically with NRG before INH and RIF challenge. The findings revealed that NRG protects against INH- and RIF-induced oxidative stress and hepatocyte apoptosis.