P316 Creation and Characterization of ATP-Binding-Cassette Transporter Knockout Rat Models

Iara D. Carbery , SAGE Labs, Sigma-Aldrich, St Louis, MO
Lara Little , Sigma-Aldrich, St Louis, MO
Edward Weinstein , Sigma-Aldrich, St Louis, MO
Xiaoxia Cui , Sigma-Aldrich, St Louis, MO
     Animal models are an essential element of drug development and toxicity assessment. Rats are preferred over mice for their closer resemblance to human anatomy and physiology and their larger size. Here we report the creation and characterization of ATP-binding-cassette (ABC) transporter knockout rats, including Mdr1a, Mrp1, Mrp2, and Bcrp using ZFN technology. Homozygous knockout animals were confirmed by the lack of respective proteins in Western Blots. Toxicology analysis showed the accumulation of ABC transporter substrates in knockout animals. In addition, we created and characterized humanized Mdr1a rats, where the human Mdr1 cDNA was site-specifically inserted under the rat Mdr1a promoter and disrupted the rat gene. Species-specific substrates and inhibitors for P-gp can be tested in this model.

 Keywords: ATP-binding cassette transporters, Mdr1a, zinc finger nuclease