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Received for publication April 6, 2007.
Revised July 3, 2007.
Accepted for publication July 9, 2007.
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 following toxic acetaminophen (APAP) ingestion, with livers from primary biliary cirrhosis (PBC) patients serving as positive controls. mRNA and protein expression of MRP1-6, MDR1-3/P-gp, and 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 to normal liver specimens, MRP1 and MRP4 mRNA levels were elevated following 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 finding 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.
Key words:
drug induced liver disease, drug-induced hepatotoxicity, hepatobiliary transport, liver injury, MRP, multi-drug resistance, p-glycoprotein
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