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Drug Metabolism and Disposition Fast Forward
First published on July 12, 2007; DOI: 10.1124/dmd.107.016170

0090-9556/07/3510-1963-1969$20.00
DMD 35:1963-1969, 2007

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Induction of Hepatobiliary Efflux Transporters in Acetaminophen-Induced Acute Liver Failure Cases

Sarah N. Barnes, Lauren M. Aleksunes, Lisa Augustine, George L. Scheffer, Michael J. Goedken, Amy B. Jakowski, Ingrid M. Pruimboom-Brees, Nathan J. Cherrington, and José E. Manautou

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.N.B., L.M.A., J.E.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (L.A., N.J.C.); Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.); and Department of Pathology and Drug Safety Research and Development, Pfizer Global Research and Development, Groton, Connecticut (M.J.G., A.B.J., I.M.P.-B.)

Alterations in transporter expression may represent a compensatory mechanism of damaged hepatocytes to reduce accumulation of potentially toxic compounds. The present study was conducted to investigate the expression of hepatobiliary efflux transporters in livers from patients after toxic acetaminophen (APAP) ingestion, with livers from patients with primary biliary cirrhosis (PBC) serving as positive controls. mRNA and protein expression of multidrug resistance-associated protein (MRP) 1-6, multidrug resistance protein (MDR) 1-3/P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) in normal (n = 6), APAP overdose (n = 5), and PBC (n = 6) human liver samples were determined by branched DNA and Western blot analysis, respectively. Double immunohistochemical staining of P-gp and proliferating cell nuclear antigen (PCNA), a marker of proliferation, was performed on paraffin-embedded tissue sections. Compared with normal liver specimens, MRP1 and MRP4 mRNA levels were elevated after APAP overdose and in PBC. Up-regulation of MRP5, MDR1, and BCRP mRNA occurred in PBC livers. Protein levels of MRP4, MRP5, BCRP, and P-gp were increased in both disease states, with MRP1 and MRP3 protein also being induced in PBC. Increased P-gp protein was confirmed immunohistochemically and was found to localize to areas of PCNA-positive hepatocytes, which were detected in APAP overdose and PBC livers. The findings from this study demonstrate that hepatic efflux transporter expression is up-regulated in cases of APAP-induced liver failure and PBC. This adaptation may aid in reducing retention of byproducts of cellular injury and bile constituents within hepatocytes. The close proximity of P-gp and PCNA-positive hepatocytes during liver injury suggests that along with cell regeneration, increased efflux transporter expression is a critical response to hepatic damage to protect the liver from additional insult.

Address correspondence to: Dr. José E. Manautou, Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Rd., Unit 3092, Storrs, CT 06269-3092. E-mail: jose.manautou{at}uconn.edu




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