title: Lipopolysaccharide exposure augments isoniazide-induced liver injury.
abstract: Isoniazide (INH) is a classic antituberculosis drug associated with clinical idiosyncratic drug-induced liver injury. It has been hypothesized that the interaction between a drug and modest inflammation results in a decreased threshold for drug toxicity. In this study, we tested the hypothesis that INH causes liver injury in rats when coadministered with lipopolysaccharide (LPS). Neither INH nor LPS alone caused liver injury. The coadministration of INH and LPS was associated with increases in serum and histopathological markers of liver injury. Tumour necrosis factor-α expression was significantly increased in the coadministered group. The downregulation of the bile acid transporter, bile salt export pump, and multidrug resistance protein 2 at both mRNA and protein levels was observed. Furthermore, the level of Farnesoid X receptor, which regulates the bile salt export pump and multidrug resistance protein 2, were clearly decreased. These results indicate that the coadministration of nontoxic doses of LPS and INH causes liver injury; the disruption of biliary excretion is considered the primary inflammation-related characteristic of INH-induced hepatotoxicity.
authors.affiliation: Jiangsu Center of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, Jiangsu Province, People's Republic of China.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Su
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D001647:Bile Acids and Salts / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007538:Isoniazid / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008111:Liver Function Tests; D008297:Male; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000995:Antitubercular Agents; D001647:Bile Acids and Salts; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D007538:Isoniazid
keywords: Cholestasis; Hepatotoxicity; Idiosyncratic drug-induced liver injury; Isoniazide; Lipopolysaccharide