ToxSci Advance Access published online on November 20, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm287
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Minimal Role Of Hepatic Transporters In The Hepatoprotection Against Lca-Induced Intrahepatic Cholestasis
* Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881
University Animal Care and Department of Veterinary Sciences/Microbiology, University of Arizona, Tucson, AZ 85721
Corresponding Author: Nathan J. Cherrington, Ph.D., Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel, Tucson, AZ 85721. Phone: (520) 626-0219 Fax: (520) 626-2466, Email: cherrington{at}pharmacy.arizona.edu
Received September 24, 2007; revision received November 15, 2007; accepted November 15, 2007
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Abstract |
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The multidrug resistance-associated proteins (Mrps) are a family of ATP-dependent transporters that facilitate the movement of various compounds, including bile acids, out of hepatocytes. The current study was conducted to determine whether induction of these transporters alters bile acid disposition as a means of hepatoprotection during bile acid-induced cholestasis. Lithocholic acid (LCA) was used to induce intrahepatic cholestasis. C57BL/6 mice were pre-treated with corn oil (CO) or known transporter inducers, phenobarbital (PB), oltipraz (OPZ) or TCPOBOP (TC) for 3 days prior to co-treatment with LCA and inducer for 4 days. Histopathology revealed that PB and TC pre-treatments provide a protective effect from LCA-induced toxicity, while OPZ pre-treatment did not. Both PB/LCA and TC/LCA co-treatment groups also had significantly lower ALT values than the LCA-only group. In TC/LCA co-treated mice compared to LCA-only, mRNA expression of uptake transporters Ntcp and Oatp4 was significantly increased, as were sinusoidal efflux transporters Mrp3 and Mrp4. While in PB/LCA co-treated mice, the only significant change compared to LCA-only treatment was an increase in uptake transporter Oatp4. Oatp1 was reduced in all groups compared to CO controls. No significant changes in mRNA expression were observed in Oatp2, Bsep, Mrp2, Bcrp, Mrp1, Mrp5 or Mrp6. Mrp4 protein expression was induced in the OPZ/LCA and TC/LCA co-treated groups, while Mrp3 protein levels remained unchanged between groups. Protein expression of Mrp1 and Mrp5 was increased in the unprotected LCA-only and OPZ/LCA mice. Thus, transporter expression did not correlate with histologic hepatoprotection, however, there was a correlation between hepatoprotection and significantly reduced total liver bile acids in the PB/LCA and TC/LCA co-treated mice compared to LCA-only. In conclusion, changes in transporter expression did not correlate with hepatoprotection, and therefore, transport may not play a critical role in the observed hepatoprotection from LCA-induced cholestasis in the C57BL/6 mouse.
Key Words: Multi-drug resistance associated protein; cholestasis; liver; bile acid.
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