QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.110106v1 319/3/1485    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zamek-Gliszczynski, M. J. Articles by Brouwer, K. L. R. Search for Related Content PubMed PubMed Citation Articles by Zamek-Gliszczynski, M. J. Articles by Brouwer, K. L. R.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Evaluation of the Role of Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 in Hepatic Basolateral Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Abcc3^–/– and Abcc4^–/– Mice

School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (M.J.Z.-G., K.N., X.T., A.S.B., K.L.R.B.); and Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania (K.L., M.G.B., G.D.K.)

Although glucuronide and sulfate conjugates of many drugs and endogenous compounds undergo appreciable hepatic basolateral excretion into sinusoidal blood, the mechanisms that govern basolateral translocation of these hydrophilic metabolites have not been completely elucidated. In the present study, the involvement in this process of Mrp3 and Mrp4, two basolateral efflux transporters, was evaluated by analyzing the hepatic basolateral excretion of the glucuronide and sulfate metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3^–/– and Abcc4^–/– mice using a cassette dosing approach. In the livers of Abcc3^–/– and Abcc4^–/– mice, the basolateral excretory clearance of acetaminophen sulfate was reduced 20 and 20%, 4-methylumbelliferyl sulfate was reduced 50 and 65%, and harmol sulfate was decreased 30 and 45%, respectively. The basolateral excretory clearance of acetaminophen glucuronide, 4-methylumbelliferyl glucuronide, and harmol glucuronide was reduced by 96, 85, and 40%, respectively, in the livers of Abcc3^–/– mice. In contrast, basolateral excretory clearance of these glucuronide conjugates was unaffected by the absence of Mrp4. These results provide the first direct evidence that Mrp3 and Mrp4 participate in the hepatic basolateral excretion of sulfate conjugates, although additional mechanism(s) are likely involved. In addition, they reveal that Mrp3 mediates the hepatic basolateral excretion of diverse glucuronide conjugates.

Address correspondence to: Dr. Kim L.R. Brouwer, University of North Carolina School of Pharmacy, Kerr Hall, CB 7360, Chapel Hill, NC 27599-7360. E-mail: kbrouwer{at}unc.edu

This article has been cited by other articles:

				N. Abla, L. W. Chinn, T. Nakamura, L. Liu, C. C. Huang, S. J. Johns, M. Kawamoto, D. Stryke, T. R. Taylor, T. E. Ferrin, et al. The Human Multidrug Resistance Protein 4 (MRP4, ABCC4): Functional Analysis of a Highly Polymorphic Gene J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 859 - 868. [Abstract] [Full Text] [PDF]

				X. Tian, B. Swift, M. J. Zamek-Gliszczynski, M. G. Belinsky, G. D. Kruh, and K. L. R. Brouwer Impact of Basolateral Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 on the Hepatobiliary Disposition of Fexofenadine in Perfused Mouse Livers Drug Metab. Dispos., May 1, 2008; 36(5): 911 - 915. [Abstract] [Full Text] [PDF]

				N. Mizuno, T. Takahashi, H. Kusuhara, J. D. Schuetz, T. Niwa, and Y. Sugiyama Evaluation of the Role of Breast Cancer Resistance Protein (BCRP/ABCG2) and Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in The Urinary Excretion of Sulfate and Glucuronide Metabolites of Edaravone (MCI-186; 3-Methyl-1-phenyl-2-pyrazolin-5-one) Drug Metab. Dispos., November 1, 2007; 35(11): 2045 - 2052. [Abstract] [Full Text] [PDF]

				A. J. Lickteig, C. D. Fisher, L. M. Augustine, L. M. Aleksunes, D. G. Besselsen, A. L. Slitt, J. E. Manautou, and N. J. Cherrington Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease Drug Metab. Dispos., October 1, 2007; 35(10): 1970 - 1978. [Abstract] [Full Text] [PDF]

				K. van de Wetering, N. Zelcer, A. Kuil, W. Feddema, M. Hillebrand, M. L. H. Vlaming, A. H. Schinkel, J. H. Beijnen, and P. Borst Multidrug Resistance Proteins 2 and 3 Provide Alternative Routes for Hepatic Excretion of Morphine-Glucuronides Mol. Pharmacol., August 1, 2007; 72(2): 387 - 394. [Abstract] [Full Text] [PDF]