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Received for publication May 31, 2005.
Revised September 6, 2005.
Accepted for publication September 28, 2005.
Multidrug resistance-associated protein (Mrp) 2-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 (P-gp), sodium-dependent taurocholate cotransporting polypeptide (Ntcp), organic anion transporting polypeptide (Oatp) 1a1 and 1a4, bile salt export pump (Bsep), breast cancer resistance protein (Bcrp), ileal bile acid transporter (Ibat), UDP-glucuronosyl transferase (UGT1a), glyceraldehyde-3-phosphate dehydrogenase, and 
-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 to wild-type controls. Likewise, the expression of UGT1a enzymes was increased in the liver and kidney of TR- rats, by ~3.5-fold 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.
Key words:
drug disposition, hepatobiliary transport, transporters, UDP glucuronyltransferases
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