RT Journal Article
SR Electronic
T1 Characterization of Multidrug Resistance 1a/P-Glycoprotein Knockout Rats Generated by Zinc Finger Nucleases
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 220
OP 227
DO 10.1124/mol.111.074179
VO 81
IS 2
A1 Chu, Xiaoyan
A1 Zhang, Zuo
A1 Yabut, Jocelyn
A1 Horwitz, Sarah
A1 Levorse, John
A1 Li, Xiang-qing
A1 Zhu, Lei
A1 Lederman, Harmony
A1 Ortiga, Rachel
A1 Strauss, John
A1 Li, Xiaofang
A1 Owens, Karen A.
A1 Dragovic, Jasminka
A1 Vogt, Thomas
A1 Evers, Raymond
A1 Shin, Myung K.
YR 2012
UL http://molpharm.aspetjournals.org/content/81/2/220.abstract
AB 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.