RGD Reference Report - Characterization of multidrug resistance 1a/P-glycoprotein knockout rats generated by zinc finger nucleases. - Rat Genome Database

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Characterization of multidrug resistance 1a/P-glycoprotein knockout rats generated by zinc finger nucleases.

Authors: Chu, X  Zhang, Z  Yabut, J  Horwitz, S  Levorse, J  Li, XQ  Zhu, L  Lederman, H  Ortiga, R  Strauss, J  Li, X  Owens, KA  Dragovic, J  Vogt, T  Evers, R  Shin, MK 
Citation: Chu X, etal., Mol Pharmacol. 2012 Feb;81(2):220-7. doi: 10.1124/mol.111.074179. Epub 2011 Nov 2.
RGD ID: 8657330
Pubmed: PMID:22049154   (View Abstract at PubMed)
DOI: DOI:10.1124/mol.111.074179   (Journal Full-text)

The development of zinc finger nuclease (ZFN) technology has enabled the genetic engineering of the rat genome. The ability to manipulate the rat genome has great promise to augment the utility of rats for biological and pharmacological studies. A Wistar Hannover rat model lacking the multidrug resistance protein Mdr1a P-glycoprotein (P-gp) was generated using a rat Mdr1a-specific ZFN. Mdr1a was completely absent in tissues, including brain and small intestine, of the knockout rat. Pharmacokinetic studies with the Mdr1a P-gp substrates loperamide, indinavir, and talinolol indicated that Mdr1a was functionally inactive in the blood-brain barrier and intestine in Mdr1a(-/-) rats. To identify possible compensatory mechanisms in Mdr1a(-/-) rats, the expression levels of drug-metabolizing enzyme and transporter-related genes were compared in brain, liver, kidney, and intestine of male and female Mdr1a(-/-) and control rats. In general, alterations in gene expression of these genes in Mdr1a(-/-) rats seemed to be modest, with more changes in female than in male rats. Taken together, our studies demonstrate that the ZFN-generated Mdr1a(-/-) rat will be a valuable tool for central nervous system drug target validation and determining the role of P-gp in drug absorption and disposition.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
establishment of blood-brain barrier  IMP 8657330 RGD 
regulation of intestinal absorption  IMP 8657330 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal blood-brain barrier function  IMP 8657330; 8657330; 8657330 RGD 
abnormal intestinal absorption  IMP 8657330; 8657330; 8657330 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcb1aem2Sage  (ATP binding cassette subfamily B member 1A; ZFN induced mutant 2, Sage)

Strains
WI-Abcb1aem2Sage  (NA)

Objects referenced in this article
Gene Abcb1aem3Sage ATP binding cassette subfamily B member 1A; ZFN induced mutant 3, Sage) Rattus norvegicus
Strain WI-Abcb1aem3Sage null Rattus norvegicus

Additional Information