%0 Journal Article %A Kevin P Forbes %A Evguenia Kouranova %A Daniel Tinker %A Karen Janowski %A Doug Cortner %A Aaron McCoy %A Xiaoxia Cui %T Creation and Preliminary Characterization of Pregnane X Receptor and Constitutive Androstane Receptor Knockout Rats %D 2017 %R 10.1124/dmd.117.075788 %J Drug Metabolism and Disposition %P dmd.117.075788 %X The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR are also involved in other endogenous processes, such as in inflammation, glucose homeostasis and lipid metabolism, and are thus potential drug targets themselves. PXR and CAR knockout and humanized mouse models have proven useful. However, the rat being bigger in size, is a preferred model system for studying drug metabolism and pharmacokinetics, allowing larger blood sampling volumes, higher accuracy in dosage, and convenient continuation into carcinogenicity testing. Here we report the creation and preliminary characterization of PXR and CAR knockout rats and PXR/CAR double knockout rats. Whereas the expression of phase I and II enzymes and transporter genes were not upregulated by nuclear receptor-specific agonists PCN and TCPOBOP in the knockout rats, confirming the disruption of respective nuclear receptor (s), our data demonstrate that PXR appears to suppress the basal expression levels of Cyp2b2, Cyp3a23/3a1, Cyp3a2, Cyp3a18 and Ugt2b1 genes, while CAR maintains Cyp2b2 and Ugt2b1 and suppresses Cyp3a9 basal expression levels. In wild type rats, agonist binding of the nuclear receptors relieves the suppression, and target genes are expressed at levels comparable to knockout rats, with or without drug treatment. Overall, our findings are in good agreement with data obtained from human primary hepatocytes, nuclear receptor knock-out cell lines and mouse knock-out models We believe these models are a useful complement to their mouse counterparts for drug development and as importantly, for functional studies on metabolic pathways involving nuclear receptors. %U https://dmd.aspetjournals.org/content/dmd/early/2017/07/17/dmd.117.075788.full.pdf