Skip Navigation



ToxSci Advance Access published online on May 8, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn093
This Article
Right arrow Advance Access manuscript (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Aleksunes, L. M
Right arrow Articles by Manautou, J. E
PubMed
Right arrow Articles by Aleksunes, L. M
Right arrow Articles by Manautou, J. E
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Acquired Resistance to Acetaminophen Hepatotoxicity is Associated with Induction of Multidrug Resistance-Associated Protein 4 (Mrp4) in Proliferating Hepatocytes

Lauren M Aleksunes*,{dagger}, Sarah N Campion*, Michael J Goedken{ddagger} and José E Manautou*

* Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269 {ddagger} Department of Pathology, Schering-Plough Research Institute, Lafayette, NJ, 07848

Corresponding author: Dr. José E Manautou, Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269-3092. Tel: 860-486-3852, Fax 860-486-5792. Email: jose.manautou{at}uconn.edu

Received March 7, 2008; revision received May 4, 2008; accepted May 5, 2008


  Abstract

Treatment with hepatotoxicants such as acetaminophen (APAP) causes resistance to a second, higher dose of the same toxicant (autoprotection). APAP induces hepatic mRNA and protein levels of the multidrug resistance-associated proteins (Mrp) transporters in mice and humans. Basolateral efflux transporters Mrp3 and Mrp4 are the most significantly induced. We hypothesized that up-regulation of Mrp3 and Mrp4 is one mechanism by which hepatocytes become resistant to a subsequent higher dose of APAP by limiting accumulation of xeno-, endobiotics and byproducts of hepatocellular injury. The purpose of this study was to evaluate Mrp3 and Mrp4 expression in proliferating hepatocytes in a mouse model of APAP autoprotection. Plasma and livers were collected from male C57BL/6J mice treated with APAP 400 mg/kg for determination of hepatotoxicity and protein expression. Maximal Mrp3 and Mrp4 induction occurred 48 h after APAP. Mrp4 up-regulation occurred selectively in proliferating hepatocytes. Additional groups of APAP-pretreated mice were challenged 48 h later with a second, higher dose of APAP. APAP-pretreated mice had reduced hepatotoxicity after APAP challenge compared to those pretreated with vehicle. A more rapid recovery of glutathione in APAP-pretreated mice corresponded with increases in glutathione synthetic enzymes. Interestingly, mice pretreated and challenged with APAP had dramatic increases in Mrp4 expression as well as enhanced hepatocyte proliferation. Inhibition of hepatocyte replication with colchicine not only restored sensitivity of APAP-pretreated mice to injury, but also blocked Mrp4 induction. Mrp4 overexpression may be one phenotypic property of proliferating hepatocytes that protects against subsequent hepatotoxicant exposure by mechanisms that are presently unknown.

Key Words: Acetaminophen; APAP; autoprotection; Mrp3; Mrp4; transporter; proliferation.

{dagger} Current address: University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics, Kansas City, KS

Email addresses: laleksunes{at}kumc.edu, sarah.campion{at}uconn.edu, michael.goedken{at}spcorp.com, jose.manautou{at}uconn.edu


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.