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Research ArticleArticle

CHARACTERIZATION OF TRANSPORT PROTEIN EXPRESSION IN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) 2-DEFICIENT RATS

Brendan M. Johnson, Peijin Zhang, John D. Schuetz and Kim L. R. Brouwer
Drug Metabolism and Disposition April 2006, 34 (4) 556-562; DOI: https://doi.org/10.1124/dmd.105.005793
Brendan M. Johnson
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Peijin Zhang
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John D. Schuetz
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Kim L. R. Brouwer
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Abstract

Multidrug resistance-associated protein (Mrp) 2-deficient transport-deficient (TR–) rats, together with their transport-competent Wistar counterparts (wild type), have been used to examine the contribution of Mrp2 to drug disposition. However, little is known about potential variation in expression of other transport proteins between TR– and wild-type rats or whether these differences are tissue-specific. Sections of liver, kidney, brain, duodenum, jejunum, ileum, and colon were obtained from male TR– and wild-type Wistar rats. Samples were homogenized in protease inhibitor cocktail and ultracentrifuged at 100,000g for 30 min to obtain membrane fractions. Mrp2, Mrp3, Mrp4, P-glycoprotein, sodium-dependent taurocholate cotransporting polypeptide, organic anion transporting polypeptides 1a1 and 1a4, bile salt export pump, breast cancer resistance protein, ileal bile acid transporter, UDP-glucuronosyl transferase (UGT1a), glyceraldehyde-3-phosphate dehydrogenase, and β-actin protein expression were determined by Western blot. Mrp3 was significantly up-regulated in the liver (∼6-fold) and kidney (∼3.5-fold) of TR– rats compared with wild-type controls. Likewise, the expression of UGT1a enzymes was increased in the liver and kidney of TR– rats by ∼3.5- and ∼5.5-fold, respectively. Interestingly, Mrp3 expression was down-regulated in the small intestine of TR– rats, but expression was similar to wild type in the colon. Mrp4 was expressed to varying extents along the intestine. Expression of some transport proteins and UGT1a enzymes differ significantly between TR– and wild-type rats. Therefore, altered drug disposition in TR– rats must be interpreted cautiously because up- or down-regulation of other transport proteins may play compensatory roles in the presence of Mrp2 deficiency.

Footnotes

  • This work was supported by National Institutes of Health Grants GM41935, GM60904, ES058571, and CA23099; by Cancer Center Support Grant P30 CA21745; and by the American Lebanese Syrian Associated Charities. B.M.J. is supported by a University of North Carolina Clinical Pharmacokinetics/Pharmacodynamics fellowship in collaboration with GlaxoSmithKline (Research Triangle Park, NC). The results of this study have been presented in part at the American Association of Pharmaceutical Scientists Annual Meetings in 2003 (Oct 26–30; Salt Lake City, UT) and 2004 (2004 Nov 7–10; Baltimore, MD).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.005793.

  • ABBREVIATIONS: Mrp, multidrug resistance-associated protein; TR–, transport-deficient; EHBR, Eisai hyperbilirubinemic rats; P450, cytochrome P450; Oatp, organic anion transporting polypeptide; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; Ntcp, sodium-dependent taurocholate cotransporting polypeptide; Bsep, bile salt export pump; TBS-T, Tris-buffered saline with Tween 20; Ibat, ileal bile acid transporter; PMSF, phenylmethanesulfonyl fluoride; UGT, UDP-glucuronosyl transferase; bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received May 30, 2005.
    • Accepted September 28, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (4)
Drug Metabolism and Disposition
Vol. 34, Issue 4
1 Apr 2006
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Research ArticleArticle

CHARACTERIZATION OF TRANSPORT PROTEIN EXPRESSION IN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) 2-DEFICIENT RATS

Brendan M. Johnson, Peijin Zhang, John D. Schuetz and Kim L. R. Brouwer
Drug Metabolism and Disposition April 1, 2006, 34 (4) 556-562; DOI: https://doi.org/10.1124/dmd.105.005793

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Research ArticleArticle

CHARACTERIZATION OF TRANSPORT PROTEIN EXPRESSION IN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) 2-DEFICIENT RATS

Brendan M. Johnson, Peijin Zhang, John D. Schuetz and Kim L. R. Brouwer
Drug Metabolism and Disposition April 1, 2006, 34 (4) 556-562; DOI: https://doi.org/10.1124/dmd.105.005793
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