The protective effects of ursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice

被引：76

作者：

Chen, Xi ^{[2
]}

Xu, Juan ^{[2
]}

Zhang, Cheng ^{[1
]}

Yu, Tao ^{[1
]}

Wang, Hua ^{[1
]}

Zhao, Mei ^{[1
]}

Duan, Zi-Hao ^{[1
]}

Zhang, Ying ^{[1
]}

Xu, Jian-Ming ^{[2
]}

Xu, De-Xiang ^{[1
]}

机构：

[1] Anhui Med Univ, Dept Toxicol, Hefei 230032, Peoples R China

[2] Anhui Med Univ, Dept Gastroenterol, Affiliated Hosp 1, Hefei 230022, Peoples R China

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2011年 / 659卷 / 01期

基金：

中国国家自然科学基金;

关键词：

UDCA (Ursodeoxycholic acid); Hepatotoxicity; Apoptosis; Antioxidant; OXIDATIVE-STRESS; PERMEABILITY TRANSITION; INDUCED APOPTOSIS; HEPATIC-INJURY; HEPATOTOXICITY; PYRAZINAMIDE; HEPATOCYTES; MECHANISMS; PREVENTION; DRUGS;

D O I：

10.1016/j.ejphar.2011.03.007

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Antitubercular drugs have been known to be potentially hepatotoxic and may lead to drug-induced liver injury. In this study, we aimed to investigate the protective effects of ursodeoxycholic acid (UDCA) on liver injury caused by co-administration with isoniazid and rifampicin, two famous antitubercular drugs. Liver injury was induced by co-treatment with isoniazid (75 mg/kg) and rifampicin (150 mg/kg) for one week. Mice were orally administered with UDCA (15,50 and 150 mg/kg) 30 min before isoniazid and rifampicin. We show that serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were significantly increased in mice treated with isoniazid plus rifampicin. An obvious fatty accumulation, accompanied by mild necrosis and inflammation, was observed in liver of mice treated with rifampicin plus isoniazid. In addition, isoniazid plus rifampicin resulted in hepatic apoptosis, as determined by terminal dUTP nick-end labeling (TUNEL) staining and caspase-3 activation. Additional experiment showed that isoniazid plus rifampicin significantly increased the level of hepatic malondialdehyde (MDA) and caused glutathione (GSH) depletion and 3-nitrotyrosine (3-NT) residues in liver. UDCA pretreatment significantly attenuated isoniazid plus rifampicin induced oxidative stress in liver. Importantly. UDCA pretreatment significantly alleviated isoniazid plus rifampicin induced hepatic apoptosis. Moreover, UDCA-mediated anti-apoptotic effect seemed to be associated with its regulation of Bcl-2 and Bax gene expression in liver. These findings suggest that UDCA might protect against isoniazid and rifampicin induced liver injury through its anti-oxidative and antiapoptotic effects. (C) 2011 Elsevier B.V. All rights reserved.

引用

页码：53 / 60

页数：8

共 35 条

[1]

p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis [J].