Document Detail

Characterization of transport protein expression in multidrug resistance-associated protein (Mrp) 2-deficient rats.
MedLine Citation:
PMID:  16204465     Owner:  NLM     Status:  MEDLINE    
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 beta-actin protein expression were determined by Western blot. Mrp3 was significantly up-regulated in the liver ( approximately 6-fold) and kidney ( approximately 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 approximately 3.5- and approximately 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.
Brendan M Johnson; Peijin Zhang; John D Schuetz; Kim L R Brouwer
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-10-04
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  34     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-22     Completed Date:  2006-09-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  556-62     Citation Subset:  IM    
School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
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MeSH Terms
ATP-Binding Cassette Transporters / genetics,  metabolism*
Brain / metabolism
Carrier Proteins / genetics,  metabolism*
Glucuronosyltransferase / metabolism
Intestines / metabolism
Kidney / metabolism
Liver / metabolism
Multidrug Resistance-Associated Proteins / metabolism
Rats, Mutant Strains
Rats, Wistar
Grant Support
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Abcc2 protein, rat; 0/Abcc4 protein, rat; 0/Carrier Proteins; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 3; EC

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