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This targeted mutation strain carries a deletion of the mouse Nr1i2 and Nr1i3 genes which encode for the nuclear receptors Pxr and Car and of the mouse aryl hydrocarbon recpetor (Ahr) gene.
Useful in defining the effect of PXR, CAR, and AHR on CYP induction and therefore pharmacokinetics, drug toxicity and efficacy.
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Genetic Background: C57BL/6 Background
The Pxr-Car-Ahr Knockout mouse was developed by Taconic in collaboration with CXR Biosciences. The triple knockout model was generated by crossing each humanized single gene mouse line with mouse lines that express a recombinase that deleted the human genes (PhiC31 deleter mouse in case of Pxr and Car, Cre deleter mouse line in case of Ahr). The three single knockout lines were then crossed together. The Humanized PXR Mouse model (Model 9104
) was created through a knock in of a human PXR cDNA/genomic construct onto the ATG of murine Pxr in C57BL/6NTac-derived ES cells. The Humanized CAR Mouse model (Model 9101
) was created through a knock in of a human CAR construct containing the genomic sequence from the translational start site on exon 2 to exon 9 onto the ATG of murine CAR in C57BL/6NTac-derived ES cells. The Humanized AHR Mouse model (Model 9165
) was created through a targeted replacement of mouse Ahr Exon 3 with a cDNA construct containing human AHR Exons 3-11 in C57BL/6NTac-derived ES cells. In all three cases targeted ES cells were injected into BALB/cJBomTac blastocysts and the resultant chimeras were backcrossed to a Flpe deleter strain on C57BL/6J to eliminate selection markers. The Pxr Knockout Mouse model was derived from the Humanized PXR Mouse line through a PhiC31-mediated deletion of the human PXR sequence. Mouse exon 2, carrying the translational start site, is deleted in the knockout, while mouse exon 1 and exons 3-9 are still present. A splice acceptor polyA motif included in the targeting vector causes splicing of exon 1 to a polyA motif and thereby terminates the transcription.
Initial Publication: Not published yet
Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N, Wolf CR. (2008) A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. J. Clin. Invest. 118(9): 3228-3239.
Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SST, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ (1995). Immune System Impairment and Hepatic Fibrosis in Mice Lacking the Dioxin-Binding Ah Receptor. Science 268: 722-726.