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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/G294    most recent 00541.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Campion, S. N. Articles by Manautou, J. E. Search for Related Content PubMed PubMed Citation Articles by Campion, S. N. Articles by Manautou, J. E.

LIVER AND BILIARY TRACT

Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function

¹Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut; ²Department of Pathology, Schering Plough Research Institute, Lafayette, New Jersey; Departments of ³Molecular Cell Biology and ⁴Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; and ⁵Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona

Submitted 19 November 2007 ; accepted in final form 9 June 2008

During acetaminophen (APAP) hepatotoxicity, increased expression of multidrug resistance-associated proteins 2, 3, and 4 (Mrp2-4) occurs. Mrp4 is the most significantly upregulated transporter in mouse liver following APAP treatment. Although the expression profiles of liver transporters following APAP hepatotoxicity are well characterized, the regulatory mechanisms contributing to these changes remain unknown. We hypothesized that Kupffer cell-derived mediators participate in the regulation of hepatic transporters during APAP toxicity. To investigate this, C57BL/6J mice were pretreated with clodronate liposomes (0.1 ml iv) to deplete Kupffer cells and then challenged with APAP (500 mg/kg ip). Liver injury was assessed by plasma alanine aminotransferase and hepatic transporter protein expression was determined by Western blot and immunohistochemistry. Depletion of Kupffer cells by liposomal clodronate increased susceptibility to APAP hepatotoxicity. Although increased expression of several efflux transporters was observed after APAP exposure, only Mrp4 was found to be differentially regulated following Kupffer cell depletion. At 48 and 72 h after APAP dosing, Mrp4 levels were increased by 10- and 33-fold, respectively, in mice receiving empty liposomes. Immunohistochemistry revealed Mrp4 staining confined to centrilobular hepatocytes. Remarkably, Kupffer cell depletion completely prevented Mrp4 induction by APAP. Elevated plasma levels of TNF- and IL-1β were also prevented by Kupffer cell depletion. These findings show that Kupffer cells protect the liver from APAP toxicity and that Kupffer cell mediators released in response to APAP are likely responsible for the induction of Mrp4.

multidrug resistance protein; hepatotoxicity; macrophage; transporter; cytokine; Abcc4