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Drug Metabolism and Disposition Fast Forward
First published on June 18, 2007; DOI: 10.1124/dmd.107.015610

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Received for publication March 7, 2007.
Revised June 15, 2007.
Accepted for publication June 15, 2007.

Hepatobiliary transporter expression in ICAM-/- and lpr mice after common bile duct ligation is independent of the degree of inflammation and oxidative stress

Martin Wagner 1, Gernot Zollner 1, Peter Fickert 1, Judith Gumhold 1, Dagmar Silbert 1, Andrea Fuchsbichler 2, Jaspreet Gujral 3, Kurt Zatloukal 2, Helmut Denk 2, Hartmut Jaeschke 4, Michael Trauner 1*

1 Div. of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz 2 Department of Pathology, Medical University Graz 3 Exponent, Inc., 320 Goddard, Suite 200, Irvine, CA 92618 4 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 101

* Address correspondence to: E-mail: michael.trauner{at}meduni-graz.at

Abstract

Liver injury in intercellular-adhesion-molecule-1 knock-out (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 not only be regulated 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, Ost{alpha}/{beta}) 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 strain. 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, while Mrp4 was only induced in the endotoxin-resistant strain. Ost{beta} was massively induced in all CBDL mice, while Ost{alpha} 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 inflammation. Rather, retention of biliary constituents may determine transporter expression in CBDL.


Key words: ABC transporters, bile acid transport, hepatobiliary transport, liver injury




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