title: The protective effects of ursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice.
abstract: 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 (75mg/kg) and rifampicin (150mg/kg) for one week. Mice were orally administered with UDCA (15, 50 and 150mg/kg) 30min 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 anti-apoptotic effects.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Zi-Hao
authors.initials: ZH
authors.lastname: Duan
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Xu
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection / Q000187:drug effects*; D004347:Drug Interactions; D005260:Female; D007538:Isoniazid / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D012293:Rifampin / Q000009:adverse effects*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D000995:Antitubercular Agents; D014580:Ursodeoxycholic Acid; D007538:Isoniazid; D012293:Rifampin