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ToxSci Advance Access originally published online on September 21, 2005
Toxicological Sciences 2006 89(2):370-379; doi:10.1093/toxsci/kfi332
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

HIGHLIGHTED ARTICLE

Coordinated Expression of Multidrug Resistance-Associated Proteins (Mrps) in Mouse Liver during Toxicant-Induced Injury

Lauren M. Aleksunes*, George L. Scheffer{dagger}, Amy B. Jakowski{ddagger}, Ingrid M. Pruimboom-Brees{ddagger} and José E. Manautou*,1

* Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269; {dagger} Department of Pathology, VU Medical Center, 1081 HV Amsterdam, The Netherlands; and {ddagger} Department of Safety Sciences, Pfizer Global Research and Development, Groton, Connecticut 06340

Received August 9, 2005; accepted September 14, 2005

Following acute chemical injury, hepatocytes are generally more resistant to toxicant re-exposure. Alterations in expression of hepatobiliary transport systems may contribute to this resistance by preventing accumulation of potentially toxic chemicals. Previous data demonstrate the concomitant reduction of uptake transporter and induction of efflux transporter mRNA during chemical liver injury. The present study further characterizes the expression of multidrug resistance-associated proteins 1–4 (Mrp1–4), breast cancer resistance protein (Bcrp) and sodium-taurocholate co-transporting polypeptide (Ntcp) in mouse liver following administration of the hepatotoxicants acetaminophen (APAP) and carbon tetrachloride (CCl4). Mice received hepatotoxic doses of APAP (400 mg/kg), CCl4 (10 or 25 µl/kg), or vehicle, ip. Livers were collected at 6, 24, and 48 h for Western blot quantification and immunofluorescence analysis. Protein expression of Bcrp was unchanged with treatment. Ntcp levels were preserved in APAP-exposed livers and reduced to 30–50% of control after CCl4. Conversely, Mrp1–4 expression was differentially up-regulated. CCl4 increased Mrp1 (3.5-fold), Mrp2 (1.4-fold), and Mrp4 (26-fold) while reducing Mrp3 levels to 20% of control. Administration of APAP enhanced expression of Mrp2 (1.6-fold), Mrp3 (3.5-fold), and Mrp4 (16-fold). Immunostaining of liver sections obtained 48 h after hepatotoxicant treatment confirmed expression patterns of a subset of transporters (Bcrp, Ntcp, Mrp3, and Mrp4). Double immunofluorescence imaging demonstrated the simultaneous down-regulation of Ntcp and up-regulation of Mrp4 in hepatocytes adjacent to the central vein after CCl4. Altered expression of transporters may reduce the overall chemical burden of an injured liver during recovery and contribute to the resistance of hepatocytes to subsequent toxicant exposure.

Key Words: acetaminophen; carbon tetrachloride; hepatotoxicity; Mrp3; Mrp4; Ntcp.


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