title: Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice.
abstract: OBJECTIVE
  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 α-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.
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors: Jittima
authors: J
authors: Weerachayaphorn
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
authors: Yuhuan
authors: Y
authors: Luo
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
authors: Albert
authors: A
authors: Mennone
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
authors: Carol J
authors: CJ
authors: Soroka
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
authors: Kathy
authors: K
authors: Harry
authors: Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA. Electronic address: james.boyer@yale.edu.
authors: James L
authors: JL
authors: Boyer
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000601:surgery; D001651:Cholestasis, Extrahepatic / Q000188:drug therapy*; D005978:Glutathione / Q000378:metabolism; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D011719:Pyrazines / Q000633:toxicity*; D013871:Thiones; D013876:Thiophenes; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D042501:Angiogenic Proteins; D001647:Bile Acids and Salts; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D016212:Transforming Growth Factor beta; C489540:Abcc4 protein, mouse; C495636:Nfe2l2 protein, mouse; C543400:mitogen-regulated protein 3, mouse; C026209:oltipraz
keywords: ALT; ANIT; AhR; BADF; BAIF; BDL; BSEP; Bile secretion; CAR; CK19; CMC; ECM; EDTA; FXR; GSH; HSC; Hepatic stellate cells; IL-1β; IL-6; Keap1; LD50; Mmp; Mrp; NAD(P)H quinone oxidoreductase; NqoI; Nrf2; OPZ; Obstructive cholestasis; Oltipraz; PBC; PDGFβ; PF; TGF-β1; TNF-α; Timp; UDCA; alanine aminotransferase; alpha smooth muscle actin; alpha-naphthylisothiocyanate; aryl hydrocarbon receptor; bile acid-dependent bile flow; bile acid-independent bile flow; bile duct ligation; bile salt efflux pump; carboxymethylcellulose; constitutive androstane receptor; cytokeratin 19; ethylenediaminetetraacetic acid; extracellular matrix; farnesoid X receptor; glutathione; hepatic stellate cells; interleukin-1 beta; interleukin-6; kelch-like ECH-associated protein 1; lethal dosage; matrix metalloproteinases; multidrug resistance-associated protein; oltipraz; platelet-derived growth factor-beta; portal fibroblasts; primary biliary cirrhosis; tissue inhibitors of metalloproteinase; transforming growth factor-beta 1; tumor necrosis factor-alpha; ursodeoxycholic acid; α-SMA
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