Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice

JOURNAL OF HEPATOLOGY

卷:60

Article

Weerachayaphorn, Jittima^1,2  Luo, Yuhuan¹  Mennone, Albert¹  Soroka, Carol J.¹  Harry, Kathy¹  Boyer, James L.¹ 

[1] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA

[2] Mahidol Univ, Fac Sci, Dept Physiol, Bangkok 10400, Thailand

关键词: Oltipraz;    Nrf2;    Obstructive cholestasis;    Bile secretion;    Hepatic stellate cells;   

DOI  :  10.1016/j.jhep.2013.08.015

来源: Elsevier

【 摘 要 】

Background & Aims: Oltipraz (4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione), a promising cancer preventive agent, has an antioxidative activity and ability to enhance glutathione biosynthesis, phase II detoxification enzymes and multidrug resistance-associated protein-mediated efflux transporters. Oltipraz can protect against hepatotoxicity caused by carbon tetrachloride, acetaminophen and alpha-naphthylisothiocyanate. Whether oltipraz has hepato-protective effects on obstructive cholestasis is unknown. Methods: We administered oltipraz to mice for 5 days prior to bile duct ligation (BDL) for 3 days. Liver histology, liver function markers, bile flow rates and hepatic expression of profibrogenic genes were evaluated. Results: Mice pretreated with oltipraz prior to BDL demonstrated higher levels of serum aminotransferases and more severe liver damage than in control mice. Higher bile flow and glutathione secretion rates were observed in unoperated mice treated with oltipraz than in control mice, suggesting that liver necrosis in oltipraz-treated BDL mice may be related partially to increased bile-acid independent flow and biliary pressure. Oltipraz treatment in BDL mice enhanced a-smooth muscle actin expression, consistent with activation of hepatic stellate cells and portal fibroblasts. Matrix metalloproteinases (Mmp) 9 and 13 and tissue inhibitors of metalloproteinases (Timp) 1 and 2 levels were increased in the oltipraz-treated BDL group, suggesting that the secondary phase of liver injury induced by oltipraz might be due to excessive Mmp and Timp secretions, which induce remodeling of the extracellular matrix. Conclusions: Oltipraz treatment exacerbates the severity of liver injury following BDL and should be avoided as therapy for extrahepatic cholestatic disorders due to bile duct obstruction. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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