| Minimal role of hepatic transporters in the hepatoprotection against LCA-induced intrahepatic cholestasis. | |
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MedLine Citation:
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PMID: 18032408 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The multidrug resistance-associated proteins (Mrps) are a family of adenosine triphosphate-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 pretreated with corn oil (CO) or known transporter inducers, phenobarbital (PB), oltipraz (OPZ), or TCPOBOP (TC) for 3 days prior to cotreatment with LCA and inducer for 4 days. Histopathology revealed that PB and TC pretreatments provide a protective effect from LCA-induced toxicity, whereas OPZ pretreatment did not. Both PB/LCA and TC/LCA cotreatment groups also had significantly lower alanine aminotransferase values than the LCA-only group. In TC/LCA cotreated mice compared with LCA only, messenger RNA (mRNA) expression of uptake transporters Ntcp and Oatp4 was significantly increased, as were sinusoidal efflux transporters Mrp3 and Mrp4. Although in PB/LCA cotreated mice, the only significant change compared with LCA-only treatment was an increase in uptake transporter Oatp4. Oatp1 was reduced in all groups compared with 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 cotreated groups, whereas 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 cotreated mice compared with 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. |
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Authors:
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Lisa D Beilke; David G Besselsen; Quiqiong Cheng; Supriya Kulkarni; Angela L Slitt; Nathan J Cherrington |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-11-20 |
Journal Detail:
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Title: Toxicological sciences : an official journal of the Society of Toxicology Volume: 102 ISSN: 1096-6080 ISO Abbreviation: Toxicol. Sci. Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-02-07 Completed Date: 2008-04-10 Revised Date: 2013-05-23 |
Medline Journal Info:
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Nlm Unique ID: 9805461 Medline TA: Toxicol Sci Country: United States |
Other Details:
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Languages: eng Pagination: 196-204 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, College of Pharmacy, University Animal Care, University of Arizona, Tucson 85721, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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metabolism Animals Bile Acids and Salts / metabolism Cholestasis, Intrahepatic / chemically induced, genetics, metabolism, pathology, prevention & control* Cytoprotection Disease Models, Animal Lithocholic Acid Liver / drug effects*, enzymology, metabolism, pathology Male Membrane Transport Proteins / biosynthesis, genetics, metabolism* Mice Mice, Inbred C57BL Multidrug Resistance-Associated Proteins / metabolism Organic Anion Transporters / metabolism Organic Anion Transporters, Sodium-Dependent / metabolism Phenobarbital / pharmacology*, therapeutic use Protective Agents / pharmacology*, therapeutic use Pyrazines / pharmacology*, therapeutic use Pyridines / pharmacology*, therapeutic use RNA, Messenger / biosynthesis Symporters / metabolism Time Factors Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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DK068039/DK/NIDDK NIH HHS; ES011646/ES/NIEHS NIH HHS; K22 ES011646/ES/NIEHS NIH HHS; K22 ES013782-01/ES/NIEHS NIH HHS; P20RR016457/RR/NCRR NIH HHS; R01 DK068039/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/Membrane Transport Proteins; 0/Multidrug Resistance-Associated Proteins; 0/Organic Anion Transporters; 0/Organic Anion Transporters, Sodium-Dependent; 0/Protective Agents; 0/Pyrazines; 0/Pyridines; 0/RNA, Messenger; 0/Symporters; 145420-23-1/sodium-bile acid cotransporter; 434-13-9/Lithocholic Acid; 50-06-6/Phenobarbital; 6N510JUL1Y/oltipraz; 76150-91-9/1,4-bis(2-(3,5-dichloropyridyloxy))benzene |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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