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Research ArticleArticle

Hepatobiliary Transporter Expression in Intercellular Adhesion Molecule 1 Knockout and Fas Receptor-Deficient Mice after Common Bile Duct Ligation Is Independent of the Degree of Inflammation and Oxidative Stress

Martin Wagner, Gernot Zollner, Peter Fickert, Judith Gumhold, Dagmar Silbert, Andrea Fuchsbichler, Jaspreet S. Gujral, Kurt Zatloukal, Helmut Denk, Hartmut Jaeschke and Michael Trauner
Drug Metabolism and Disposition September 2007, 35 (9) 1694-1699; DOI: https://doi.org/10.1124/dmd.107.015610
Martin Wagner
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Gernot Zollner
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Peter Fickert
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Judith Gumhold
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Dagmar Silbert
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Andrea Fuchsbichler
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Jaspreet S. Gujral
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Kurt Zatloukal
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Helmut Denk
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Hartmut Jaeschke
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Michael Trauner
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Abstract

Liver injury in intercellular adhesion molecule 1 knockout (ICAM-/-) and Fas receptor-deficient (lpr) mice is markedly reduced after common bile duct ligation (CBDL) due to significantly reduced inflammation and oxidative stress. Liver injury in CBDL rodents is counteracted by adaptive hepatobiliary transporter induction. Since hepatobiliary transporter expression in obstructive cholestasis may be regulated not only by accumulating bile acids but also by inflammatory mediators and oxidative stress, we hypothesized that differences in the inflammatory response may affect hepatobiliary transporter expression in CBDL, which would contribute to reduced liver injury. Therefore, expression of major hepatobiliary transporters (Ntcp, Bsep, Mrp2-4, Ostα/β) was determined by Taqman RT-PCR and Western blotting in sham-operated animals and 3 days after CBDL in wild-type, ICAM-/- and lpr mice of the endotoxin-sensitive C57BL/6 and the endotoxin-resistant C3H/HeJ strains. CBDL resulted in a significant decrease of Ntcp in all genotypes. Canalicular transporters Bsep and Mrp2 were repressed only in the endotoxin-sensitive strain regardless of the genotype. Mrp3 was moderately induced in ICAM-/-, lpr, and endotoxin-resistant mice, whereas Mrp4 was only induced in the endotoxin-resistant strain. Ostβ was massively induced in all CBDL mice, whereas Ostα was reduced. In conclusion, markedly reduced inflammation and oxidative stress in CBDL ICAM-/- and lpr mice does not profoundly affect hepatobiliary transporter expression. Therefore, transporter expression does not account for reduced liver injury in ICAM-/- and lpr mice. Induction of the adaptive transporter response after CBDL is independent of the degree of the inflammatory response. Rather, retention of biliary constituents may determine transporter expression in CBDL.

Footnotes

  • This work was supported by Grant P18613-B05 from the Austrian Science Foundation and by National Institutes of Health Grant AA-12916.

  • doi:10.1124/dmd.107.015610.

  • ABBREVIATIONS: ABC, ATP-binding cassette; Bsep (Abcb11), bile salt export pump; CBDL, common bile duct ligation; ICAM-1, intercellular adhesion molecule 1; lpr mice, Fas receptor-deficient mice; Mrp, multidrug resistance-associated protein; Ntcp (Slc10a1), Na+/taurocholate cotransporter; Oatp, organic anion transporter; Ost, organic solute transporter.

    • Received March 6, 2007.
    • Accepted June 15, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (9)
Drug Metabolism and Disposition
Vol. 35, Issue 9
1 Sep 2007
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Research ArticleArticle

Hepatobiliary Transporter Expression in Intercellular Adhesion Molecule 1 Knockout and Fas Receptor-Deficient Mice after Common Bile Duct Ligation Is Independent of the Degree of Inflammation and Oxidative Stress

Martin Wagner, Gernot Zollner, Peter Fickert, Judith Gumhold, Dagmar Silbert, Andrea Fuchsbichler, Jaspreet S. Gujral, Kurt Zatloukal, Helmut Denk, Hartmut Jaeschke and Michael Trauner
Drug Metabolism and Disposition September 1, 2007, 35 (9) 1694-1699; DOI: https://doi.org/10.1124/dmd.107.015610

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Research ArticleArticle

Hepatobiliary Transporter Expression in Intercellular Adhesion Molecule 1 Knockout and Fas Receptor-Deficient Mice after Common Bile Duct Ligation Is Independent of the Degree of Inflammation and Oxidative Stress

Martin Wagner, Gernot Zollner, Peter Fickert, Judith Gumhold, Dagmar Silbert, Andrea Fuchsbichler, Jaspreet S. Gujral, Kurt Zatloukal, Helmut Denk, Hartmut Jaeschke and Michael Trauner
Drug Metabolism and Disposition September 1, 2007, 35 (9) 1694-1699; DOI: https://doi.org/10.1124/dmd.107.015610
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